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COLLEGE  OF  PHYSICIANS 
AND   SURGEONS 


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PHYSIOLOGY  AND  BIOCHEMISTRY 
IN  MODERN  MEDICINE 


BY 

J.  .J.  B.  MACLEOD,  M.B. 

PROFESSOR   OF  PHYSIOLOGY   IN    THE   UNIVERSITY  OF  TORONTO,   TORONTO,   CANADA;    FORMERLY 

PROFESSOR    OF    PHYSIOLOGY    IN    THE    WESTERN    RESERVE    UNIVERSITY, 

CLEVELAND,   OHIO 


Assisted  by  Roy  G.  Pearce,  B.A.,  M.D. 
Director    of    the    Cardiorespiratory  Laboratory    of    Lakeside    Hospital, 

Cleveland,  Ohio 

ANT)  BY  OTHERS 


11777/  233  ILLUSTRATIONS,  INCLUDING 
11  PLATES  IN  COLORS 


ST.  LOUIS 

C.  V.  MOSBY  COMPANY 
1918 


if 


Copyright,   1918,  By   C.   V.   Mosby  Company 


Press  of 

C.  V.  Mosby  Company 

St.  f.  ou  is 


TO 
M.  W.  M. 


PREFACE 

"The  necessity  of  allotting  the  various  subjects  of  the  medical  curric- 
ulum to  different  periods,  so  that  the  more  strictly  scientific  subjects 
are  completed  in  the  earlier  years,  has  the  great  disadvantage  that  the 
student,  being  no  Longer  in  touch  with  laboratory  work,  fails  to  employ 

the  scientific  knowledge  with  full  advantage  in  the  solution  of  his  clin- 
ical problems.  He  is  apt  to  regard  the  first  two  or  three  years  in  the 
laboratory  departments  as  inconsequential  in  comparison  with  the  sup- 
posedly more  practical  instruction  offered  during  the  subsequent  clinical 
years.  He  is  taught  by  his  laboratory  instructors  to  observe  accurately, 
and  to  correlate  the  observed  facts,  so  that  he  may  be  enabled  to  draw 
conclusions  as  to  the  manner  of  working  of  the  various  functions  of  the 
animal  body  in  health,  and  before  proceeding  to  his  clinical  studies,  he 
is  required  to  show  a  proficiency  in  scientific  knowledge,  because  it  is 
recognized  that  this  must  serve  as  the  basis  upon  which  his  knowledge 
of  disease  is  to  be  built.  "When  the  clinic  is  reached,  however,  the  meth- 
ods of  the  scientist  are  not  infrequently  cast  aside  and  an  understanding 
of  disease  is  sought  for  largely  by  the  empirical  method;  namely,  by  the 
endeavor  to  see  and  examine  innumerable  patients,  to  diagnose  the  case 
according  to  the  grouping  of  the  signs  and  symptoms,  and  to  treat  it  by 
the  prescribed  methods  of  experience.  So  much  has  to  be  learned  and  so 
much  has  to  be  seen  during  the  clinical  years,  that  the  student  yives  little 
thought  to  the  nature  of  the  functional  disturbance  which  is  responsible 
for  the  symptoms-,  he  fails  to  realize  that  after  all,  there  is  no  essen- 
tial difference  between  the  condition  brought  about  in  his  patient  by 
some  pathologic  lesion,  and  that  which  may  be  produced  in  the  labora- 
tory by  experimental  procedures,  by  drugs  or  by  toxins.  It  must  of 
course  be  recognized  that  just  as  the  science  of  medicine  originated  by 
the  grouping  of  symptoms  into  more  or  less  characteristic  diseases  for 
which  the  most  favorable  method  of  treatment  had  to  be  discovered  by 
experience,  so  must  a  certain  part  of  the  medical  training  be  more  or 
less  empirical  but  it  should  at  the  same  time  be  realized  that  such  a 
method  is  only  a  means  to  an  end,  and  that  the  real  understanding  of 
disease  can  be  acquired  only  when  every  abnormal  condition  is  inter- 
preted as  a  primary  or  secondary  consequence  of  some  perverted  bodily 
function,  and  when  the  training  in  observation  and  the  inductive  method 
is  carried  from  the  laboratory  into  the  clinic. 


VI  PREFACE 

It  is  a  constant  experience  of  clinical  instructors  who  would  employ 
scientific  methods  of  instruction,  that  they  find  the  students  no1  only 
indifferent  to  an  analysis  of  their  cases  from  the  functional  standpoint, 
but  also  that  they  are  too  inadequately  prepared  in  fundamental  phys- 
iologic knowledge,  to  make  the  analysis  possible.  The  student  may 
have  a  superficial  acquaintance  with  the  main  facts  of*  physiologic  science 
but  have  failed  to  acquire  the  enquiring  habit  of  mind  which  will  en- 
able him;  through  reflection,  comparison,  and  personal  research,  to  ap- 
ply the  knowledge  in  practical  medicine  and  surgery. 

For  this  lack  of  con-elation  between  the  laboratory  and  clinical  stud- 
ies, the  clinical  instructors  are  not  alone  responsible.  The  laboratory 
courses  are  frequently  given  without  any  attempt  being  made  to  show 
the  student  the  bearing  of  the  subject  in  the  interpretation  of  disease, 
or  to  train  him  so  that  in  his  later  years  he  may  be  able  to  adapt  the 
methods  of  investigation  which  he  learned  in  the  laboratory,  to  the  study 
of  morbid  conditions.  It  is  self-evident  that  (without  any  knowledge 
of  disease)  the  extent  to  which  the  student  in  the  earlier  years  of  the 
course  could  be  expected  to  appreciate  the  clinical  significance  of  what 
he  learns  in  the  laboratory  is  limited,  but  this  should  not  deter  the  in- 
structor from  indicating  Avhenever  he  can,  the  general  application  of 
scientific  knowledge  in  the  interpretation  of  diseased  conditions.  But 
the  chief  remedy  of  the  evil  undoubtedly  lies  partly  in  the  continuance 
of  certain  of  the  laboratory  courses  into  the  clinical  years,  and  partly 
in  the  study  of  medical  literature  in  which  the  application  of  physiology 
and  biochemistry  in  the  practice  of  medicine  is  emphasized. 

Notwithstanding  the  sufficient  number  of  excellent  textbooks  in  phys- 
iology available  to  the  medical  student,  there  is  none  in  which  partic- 
ular emphasis  is  laid  upon  the  application  of  the  subject  in  the  routine 
practice  of  medicine.  In  the  present  volume  the  attempt  is  made  to 
meet  such  a  want,  by  reviewing  those  portions  of  physiology  and  bio- 
chemistry which  experience  has  shown  to  be  of  especial  value  to  the 
clinical  investigator.  The  work  is  not  intended  to  be  a  substitute, 
either  for  the  regular  textbooks  in  physiology,  or  for  those  in  functional 
pathology,  Tt  is  supplementary  to  such  volumes.  It  does  not  start  like 
the  modern  test  in  functional  pathology,  with  a  consideration  of  the 
diseased  condition,  and  then  proceed  to  analyze  the  possible  causes  and 
consequences  of  the  disturbances  of  function  which  this  exhibits;  but 
it  deals  with  the  present-day  knowledge  of  human  physiology  in  so  far 
as  this  can  be  used  in  a  general  way  to  advance  the  understanding  of 
disease.  In  a  sense  it  is  therefore  an  advanced  text  in  physiology  for 
those   about    to   enter   upon   their   clinical    instruction,   and    at    the   same 


PREFACE  Vll 

time,  a  review  for  those  of  a  maturer  clinical  experience  who  may  desire 
to  seefc  tlic  physiological  interpretation  of  diseased  conditions. 

In  attempting  to  fulfil  these  requirements,  it  has  been  deemed  essen- 
tial to  go  back  to  the  fundamentals  of  the  subject,  and  to  explain  as 
Bimply  as  possible  the  physical  and  physicochemical  principles  upon 
which  so  large  a  part  of  physiological  knowledge  depends.  Physiology 
may  be  considered  as  an  application  of  the  known  laws  and  facts  of 
physics  and  chemistry  to  explain  the  functions  of  living  matter,  and  it  is 
only  after  the  extent  to  which  this  application  can  be  made  has  been 
appreciated,  that  the  knowledge  may  be  used  to  serve  as  the  foundation 
upon  which  a  superstructure  of  clinical  knowledge  can  be  built. 

In  order  that  the  volume  might  be  maintained  of  reasonable  size,  it 
has  been  necessary  to  select  certain  parts  of  the  subject  for  particular 
emphasis,  the  basis  of  selection  being  the  degree  to  which  our  knowledge 
clearly  shows  the  value  of  the  application  of  physiological  methods  both 
of  observation  and  of  thought  in  the  study  of  diseased  conditions.  This 
has  not  been  done  to  the  extent  of  omitting  the  apparently  less  essential 
parts,  for  these  have  been  treated  in  sufficient  detail  to  link  the  others 
together  so  as  to  preserve  a  logical  continuity,  and  show  the  bearing  of 
one  field  of  knowledge  on  another.  There  are  however  certain  parts 
of  the  science,  particularly  the  physiology  of  nerve  and  muscle,  of  the 
special  senses,  and  of  reproduction,  for  which  application. in  the  general 
fields  of  medicine  and  surgery  is  limited,  and  these  parts  have  been 
omitted  entirely.  It  has  been  judged  that  this  perhaps  somewhat  arbi- 
trary selection  is  justified  on  the  ground  that  the  ordinary  text  in 
physiology  covers  these  subjects  sufficiently,  except  for  the  specialist, 
for  whom  on  the  other  hand,  no  adequate  review  would  have  been  pos- 
sible within  the  limits  of  such  a  volume  as  this.  With  reference  to  bio- 
chemistry,  no  attempt  is  made  to  review  the  properties  or  describe  the 
characteristic  tests  of  the  various  chemical  ingredients  of  the  body  tis- 
sues and  fluids.  This  is  already  sufficiently  done  in  the  textbooks  on 
biochemistry,  and  in  the  numerous  manuals  on  clinical  methods.  Bio- 
chemical knowledge  is  treated  rather  from  the  physiologist's  stand- 
point, as  an  integral  part  of  his  subject,  particular  attention,  neverthe- 
less, being  paid  to  the  far-reaching  applications  of  this  latest  depart- 
ment of  medical  science,  in  the  elucidation  of  many  obscure  problems 
of  clinical  medicine,  such  as  those  of  diabetes,  nephritis,  acidosis,  goiter 
and  myxedema.  To  make  the  volume  of  value  to  those  who  may  not 
have  had  time  or  opportunity  to  familiarize  themselves  with  the  techni- 
cal methods  of  the  physiologist  and  biochemist  as  used  in  the  modern 
clinic,  a  certain  amount  of  space  is  devoted  to  a  brief  description  of  the 
methods  that  appear  at  present  to  be  receiving  most  attention,  and  to 
be  of  greatest  value. 


vill  PREFACE 

Finally,  il  should  be  mentioned  that  the  principles  of  serum  diagnosis 
and  therapy  are  omitted,  since  these  belong  to  a  highly  specialized  science 
requiring  an  intensive  training  of  its  own. 

In  the  hope  that  the  volume  may  be  instrumental  in  arousing  sufficient 
interest  to  stimulate  a  more  intensive  study  of  the  various  subjects 
which  it  introduces,  a  brief  bibliography  is  given  at  the  end  of  each 
section.  The  references  selected  are  to  papers  that  are  more  partie- 
nlarly  known  to  the  author;  they  are  not  necessarily  the  most  impor- 
tant publications  on  the  subject,  but  are  often  chosen  because  of  the 
useful  reviews  of  previous  work  contained  in  them,  rather  than  because 
of  their  own  originality.  Some  of  the  papers,  however,  are  referred  to 
as  authority  for  statements  of  fact  which  may  arouse  in  the  reader  a 
desire  to  ponder  for  himself  the  evidence  upon  which  these  are  based. 
The  references  are  usually  divided  into  two  groups,  "monographs"  and 
"original  papers,"  and  it  is  only  occasionally  that  specific  reference  is 
made  to  the  former  in  the  context.  The  original  papers,  on  the  oilier 
hand,  are  referred  to  by  numbers.  With  the  general  field  of  the  subject 
so  well  covered  by  such  excellent  textbooks  as  Bayliss'  "Principles  of 
General  Physiology,"  Stewart's,  Howell's,  Starling's,  and  Halliburton's 
"Human  Physiologies,"  and  Leonard  Hill's  "Recent  and  Further  Ad- 
vances in  Physiology,"  the  author  has  felt  free  to  pick  and  choose  from 
the  monographs  and  original  papers,  topics  that  are  ordinarily  passed 
over  cursorily  in  the  textbook,  and  when  this  has  been  done,  the  refer- 
ences are  somewhat  more  extensive.  Such  is  the  case  for  example  in 
the  chapters  relating  to  the  chemistry  of  respiration,  to  the  metabolism 
of  carbohydrates  and  fats,  to  the  problems  of  dietetics  and  growth,  to  the 
physicochemical  basis  of  neutrality  regulation  in  the  animal  body,  and  to 
the  action  of  enzymes. 

Acknowledgment  is  gratefully  made  for  the  assistance  and  advice 
in  the  preparation  of  the  book,  particularly  to  Doctor  R.  Gr.  Pcarce,  for 
the  contribution  of  several  chapters,  to  which  his  name  is  attached,  and 
for  which  he  is  entirely  responsible;  and  to  Doctor  E.  P.  Carter,  whose 
criticisms,  after  patient  perusal  of  the  unfinished  manuscript,  were  of 
inestimable  value  in  its  final  revision.  Acknowledgment  is  also  made 
to  Doctor  R.  W.  Scott  and  Professor  F.  E.  Lloyd,  for  valuable  criticism 
and  advice,  and  to  the  former  for  a  chapter  on  the  "Clinical  Applica- 
tion of  Electrocardiographs."  To  Miss  Achsa  Parker,  M.A.,  the  author 
owes  a  great  debt  of  gratitude  for  the  thorough  and  painstaking  way  in 
which  she  prepared  the  manuscript  for  the  press,  and  for  her  never- 
tiring  endeavors  to  have  the  spelling  and  punctuation  in  conformity 
with  Webster's  Dictionary.  For  assistance  in  the  preparation  of  the 
index  thanks  are  due  to  Miss  Marian   Armour  and   Mrs.   MacFarlane, 


PREFACE  ix 

and  for  permission  to  use  certain  of  the  figures  and  illustrations,  to  the 
various  authors  and  publishers  who  granted  it.  For  the  excellent  man- 
agement and  careful  execution  of  the  presswork,  the  author  wishes  to 
thank  the  publishers,  whose  courteous  and  friendly  dealings  have  always 
made  the  work  easier. 

J.  J.  R.  Macleod. 

University  of  Toronto, 
Toronto,  Canada. 


CONTENTS 


I 'ART  I 

THE  PHYSICOCHEMICAL  BASIS  OF  PHYSIOLOGICAL 

PROCESSES 

CHAPTER  I                                                        page 
General    Considerations 1 

The  Laws  of  Solution,  3 ;  Gas  Laws,  3 ;  Osmotic  Pressure,  4 ;  Biological  Methods 
for  Measuring  Osmotic  Pressure,  6;  Hemolysis,  7;  Plasmolysis,  8. 

CHAPTER  II 

Osmotic   Pressure   (Cont'd) 10 

Measurement  by  Depression  of  Freezing  Point,  10 ;  The  Role  of  Osmosis  Dif- 
fusion,  and  Allied  Processes   in   Physiologic  Mechanisms,   11. 

CHAPTER  III 

Electric  Conductivity,  Dissociation,  and   Ionization 16 

Biological  Applications,  19. 

CHAPTER  IV 

The  Principles  Involved  in  the  Determination  of  Hydrogen-ion  Concentration  22 
Titrable  Acidity  and  Alkalinity,   22;   Actual  Degree   of  Acidity  or  Alkalinity, 
23;  Mass  Action,  23;   Application  to  the  Measurement  of  H-ion  Concentration, 
26;  Application  in  Determining  the  Real  Strength  of  Acids  or  Alkalies,  28. 

CHAPTER  V 
The  Principles  Involved  in  the  Measurement  op  Hydrogen-ion  Concentration 

(Cont'd) 29 

The  Electric  Method,  29 ;  The  Indicator  Method,  32. 

CHAPTER  VI 

Regulation   of    Neutrality    in    the   Animal   Body    and   Acidosis 36 

Buffer  Substances,  36;  Theory  of  Acidosis,  38;  Measurement  of  the  Reserve 
Alkalinity,  41  ;  Titration  Methods,  41;  O02-combining  Power,  42;  Indirect 
Methods,  46. 

CHAPTER  VII 
Colloids ■ 50 

Characteristic  Properties,  50;  Charack'iistics  of  True  Colloidal  Solutions, 
51;  Tyndall  Phenomenon,  51;  Relative  Indiffusibility,  51;  Electric  Proper- 
ties, 55;   Brownian   Movement,   57;    Osmotic  Pressure.   57. 

xi 


Xll  CONTENTS 

CHAPTER  VIII  page 

Colloids  (Cont'd) GO 

Suspensoids  and  Emulsoids,  60;  Gelatinization,  61;  Imbibition,  62;  Action  of 
Electrolytes  on  Colloids,  63;  Proteins  as  Colloids,  63;  Surface  Tension,  64; 
Adsorption,  65;  Everyday  Reactions  Depending  on  Adsorption,  66;  Conditions 
Influencing  or  Influenced  by  Adsorption,  67;  Physiologic  Processes  Depending 
on  Adsorption,  69. 

CHAPTER  IX 

Ferments,   or   Enzymes 71 

The  Nature  of  Enzyme  Action,  72 ;  Properties  of  Enzymes,  73 ;  Reversibility 
of  Enzyme  Action,  77;  Specificity  of  Enzyme  Action,  79;  Peculiarities  of 
Enzymes,  80 ;  Types  of  Enzyme,  81 ;  Enzyme  Preparations,  82 ;  Conditions  for 
Enzymic  Activity,  82 


PART  II 
THE  CIRCULATING  FLUIDS 

CHAPTER  X 

Blood:   Its  General  Properties   (By  R.  G.  Pearce) 83 

Quantity  of  Blood  in  the  Body,   85;   Water  Content,  86;   Proteins,  87;   Fer- 
ments and  Antiferments,  89. 

CHAPTER  XI 

The  Blood  Cells  (By  R.  G.  Pearce) 91 

Red  Blood  Corpuscles,  or  Erythrocytes,  91;  Origin,  92;  Rates  of  Regeneration, 
93;  Hemolysis,  95;  Leucocytes,  96;  Blood  Platelets,  97. 


CHAPTER  XII 


98 


Blood  Clotting 

Visible  Changes  in  the  Blood  During  Clotting,  98;  Methods  of  Retarding 
Clotting,  99 ;  Nature  of  the  Clotting  Process,  101 ;  Influence  of  Calcium  Salts, 
103;   Influence  of  Tissues,  104. 

CHAPTER  XIII 

Blood   Clotting    (Cont'd) 10(> 

Theories  of  Blood  Clotting,  106;  Intravascular  Clotting,  107;  Measurement  of 
the  Clotting  Time,  108;  Blood  Clotting  in  Various  Physiologic  Conditions,  110; 
Blood  Clotting  in  Disease,  111;  Hemorrhagic  Diseases,  112;  Thrombus  Forma- 
tion, 113.  jj 

CHAPTER  XIV 

Lymph  Formation    and    Circulation U5 

General  Considerations,   115;    Experimental   Investigations,    118;   Edema,    120. 


CONTENTS  \iii 

PART   III 
CIRCULATION  OF  THE  BLOOD 

CHAPTER   XV  PAGE 

Blood   Pressure 122 

The  Mean  Arterial  Blood  Pressure,  li'.'i;  Mercury  Manometer  Tracings,  U.'i; 
Spring  Manometer  Tracings,  126;  Clinical  Measurements,  128. 

CHAPTER  XVI 

The  Factors  Concerned  in  Maintaining  the  Blood  Pressure 1::  l 

Pumping  Action  of  the  Heart,  134;  Peripheral  Resistance,  134;  Amount  of 
Blood  in  the  Body,  135;  Effects  of  Hemorrhage  and  Transfusion,  139;  Viscos- 
ity of  the  Blood,  140;    Elasticity   of   Vessel  Walls,    Ml'. 

CHAPTER   XVII 

The  Action-  of  the  Heart 144 

The  Pumping  Action  of  the  Heart,  144;  Intracardiac  Pressure.  Curves,  146; 
Comparison  of  the  Curves,  lis. 

CHAPTER  XVIII 

The   Pumping  Action  of  the  Heart   (Cont'd) 151 

Contour  of  the  Intracardial  Pressure  Curves,  151;  Ventricular  Curve,  151; 
Auricular  Curve,  153;  The  Mechanism  of  Opening  and  Closing  .of  the  Valves, 
154;  The  Heart  Sounds,  157;  Causes  of  Sounds,  157;  Records  of  Sounds 
(Electrophonograms),  158. 

CHAPTER  XIX 

The   Nutrition    of    the    Heart 161 

Blood  Supply,  161 ;  Perfusion  of  the  Heart  Outside  the  Body,  161 ;  Resuscita- 
tion of  the  Heart  in  Situ,  164;  Relationship  of  the  Chemical  Composition  of  the 
Perfusion  Fluid  in  Cold-blooded  and  Warm-blooded  Hearts,  165. 

CHAPTER  XX 

Physiology  of    the    Heartbeat 170 

Origin  and  Propagation  of  the  Beat,  170;  Myogenic  Hypothesis,  171;  Neuro- 
genic Hypothesis,  172;  The  Pacemaker  of  the  Heart  and  Heart-block,  174; 
Physiologic  Characteristics  of  Cardiac  Muscle,  176. 

CHAPTER   XXI 

Physiology  of  the  Heartbeat  (Cont'd) 1S2 

Origin  and  Propagation  of  the  Beat  in  the  Mammalian  Heart,  182;  Conduct- 
ing Tissue  in  the  Mammalian  Heart,  182;   Site  of  Origin  of  Beat,  1S7. 

CHAPTER  XXII 
Physiology  of  the  Heartbeat  (Cont'd) 191 

Mode  of  Propagation  of  the  Beat  in  the  Auricles  and  from  the  Auricles  to  the 
Ventricles,  191;  Spread  of  Beat  in  the  Ventricle,  103;  Fibrillation  of  the  Ven- 
tricles  and   Auricles,    195. 


xiv  CONTENTS 

CHAPTER  XXIII  PAOT 

The   Bloodplow   in   the  Arteries .  igg 

The  Pulses,  108;  General  Characteristics,  198;  Rate  of  Transmission  of   Pulse 

Waves,  198;  Contour  of  the  Pulse  Curve,  200;  Velocity  Pulse,  200;  Palpable 
Pulse,  202;  Analysis  of  the  Curve,  202;  The  Dicrotic  Wave,  20.°.;  Causes  of 
Disappearance  of  the  Pulse  in  the  A'eins,  205. 

CHAPTER  XXIV 

Rate  of  Movement  of  the  Blood  in  the  Blood  Vessels 200 

Velocity  of  Flow,  206 ;  Mass  Movement  of  the  Blood,  208 ;  The  Visceral  Blood- 
flow  in  Man,  212;  Work  of  the  Heart,  212;  Circulation  Time,  213;  Movement 
of  Blood   in   the  Veins,   214. 

CHAPTER   XXV 

The  Control  of  the  Circulation 210 

Nerve  Control,  217;  Vagus  Control  in  the  Cold-blooded  and  the  Mammalian 
Heart,  217;  Tonic  Vagus  Action,  221;  Afferent  Vagus  Impulses,  222:  Mechan- 
ism of  Vagus,  224;  Termination  of  the  Vagus  Fibers  in  the  Heart,  225;  Sym- 
pathetic Control.  227. 

CHAPTER  XXVI 

The  Control  of  the  Circulation  (Cont'd) 220 

Nerve  Control  of  Peripheral  Resistance,  229;  Detection  of  Vasomotor  Fibers 
in   Nerves,   231 ;    Origin   of  Vasomotor  Nerve   Fibers,   232 ;    Vasomotor    \ 
Centers,  235 ;  Independent  Tonicity  of  Blood  Vessels,  236. 

CHAPTER  XXVII 


The  Control  of  the  Circulation  (Cont'd) 237 

Control  of  the  Vasomotor  Center,  237;  Hormone  Control,  237;  Nerve  Control, 
238 j  Pressor  and  Depressor  Impulses,  239;  Reciprocal  Innervation  of  Vascular 
Areas.  243;   Influence  of  Gravity  on  the  Circulation,  244. 

CHAPTER  XXVIII 

Peculiarities  of  Blood  Supply  in  Certain  Viscera 247 

Circulation  in  the  Brain,  247;  Anatomical  Peculiarities,  247;  Physical  Condi- 
tions of  Circulation,  249;  Vasomotor  Nerves.  252;  Intracranial  Pressure,  25.".; 
Circulation  through  the  Lungs,  253;  Circulation  through  the  Liver,  255;  The 
Coronary  Circulation,  257. 

CHAPTER  XXIX 

Clinical  Applications  of  Certain   Physiologic   Methods 250 

Electrocardiograms,    250;    The   Ventricular    Complex,    262. 

CHAPTER  XXX 

Clinical  Applications  of  Certain  Physiologic  Methods  (Cont'd) 266 

Electrocardiograms  of  the  More  Usual  Forms  of  Cardiac  Irregularities,  266; 
Sinus  Arrhythmia,  266;  Sinus  Bradycardia,  266;  The  Extrasystole,  266;  Parox- 
ysmal Tachycardia.  200;  Auricular  Fibrillation,  200;  Auricular  Flutter.  269; 
Heart-block,  270. 


CONTENTS  XV 

CHAPTER   XXXI  PAGE 

Clinical  Applications  of  Certain  Physiologic  Methods  (Cont'd) 273 

Polysphygmograms,  273;  Venous  Pulse  Tracings,  27.".:  Simultaneous  Arterial 
Pulse  Tracings,  276;  Abnormal  Pulses,  276. 

CHAPTEB   XXXII 

Clinical  Applications  of  Certain  Physiologic  Methods  (Cont'd) 281 

Measurement  of  the  Muss  Movement  of  t he  Blood,  2sl;  The  Normal  Flow, 
282  j  Clinical  Conditions  Which  Affect   the   BloodEow,  '2s?,. 

CHAPTEB  XXXIII 

k :>7 

Gravity  Shock,  287 ;  Hemorrhage  Shock,  288;  Anesthetic  Shock,  288;  Spinal 
Shock,  2SS;  Nervous  Shock,  289;  Surgical  Shock,  289;  Experimental  In- 
vestigation of  Shock,  289;  Treatment,  205;  Cause  of  Secondary  Symptoms, 
295. 


PART  IV 

RESPIRATION 

CHAPTER  XXXIV 

Respiration 299 

The  Mechanics  of  Respiration,  299;  Pressure  and  Amount  of  Air  in  the  Lungs, 
299 ;  Respiratory  Tracings,  303 ;  The  Intrapleural  Pressure,  304 ;  Influence 
on  Blood  Pressure,  306. 

CHAPTER  XXXV 

The  Mechanics  ok  Respiration   (Cont'd)    (By  R.  G.  Pearce) 310 

Variations  in  Dead  Space,  Residual  Air  and  the  Mid-  and  Vital  Capacities  in 
Various  Physiologic  and  Pathologic  Conditions,  310. 

CHAPTER  XXXVI 

The  Mechanics  of  Respiration-   (Cont'd)    (By  R.  G.  Pearce) 315 

The  Mechanism  of  the  Changes  in  Capacity  of  the  Thorax  and  Lungs,  315; 
The  Movements  of  the  Ribs,  315;  The  Action  of  the  Musculature  of  the  Rilis, 
319;  The  Action  of  the  Diaphragm,  320;  The  Effects  of  the  Respiratory  Move- 
ments on  the  Lungs,  325. 

CHAPTEB  XXXVII 

Tin;  Control  of  Bespiration 327 

The  Eespiratory  Centers,   327;   Reflex  Control  of  the  Respiratory  Center,  331. 

CHAPTER  XXXVIII 

The   Control   of   Respiration    (Cont'd) "...  335 

Hormone  Control  of  the  Respiratory  Center,  335;  Tension  of  CO.  and  02  in 
Arterial  Blood,  337;  Tension  of  CO,  and  O,  in  Alveolar  Air,  339;  Tension  of 
CO,  in  Venous  Blood,  342. 


\\i  CONTENTS 

CHAPTEB    XX XIX  PAGE 

The  Control  op  Respiration  (Cont'd)   (By  B.  G.  Pf.arce) 344 

Estimation  of  the  Alveolar  Gases,  -".it:  Method  for  Normal  Subjects,  345 ; 
Clinical  Method,  3  17. 

CHAPTER  XL 

Tin:  Control  op   Respiration    (Cont'd) P.40 

The  Nature  of  the  Respiratory  Hormone,  349;  Relationship  between  C03  of 
Inspired  Air  and  Pulmonary  Ventilation,  350;  Possibility  that  CO=  Specifically 
Stimulates  tlic  Center,  352;  Relationship  among  Acidosis,  Alveolar  CO.  and 
Respiratory  Activity,  354. 

CHAPTER  XLI 

The  Control  ok  Respiration    (Cont'd) 356 

The  Constancy  of  the  Alveolar  C02  Tension  under  Normal  Conditions,  23<\; 
Sensitivity  of  the  Center  to  Changes  in  the  CO,  Tension  of  the  Alveolar  Air, 
.".•17;  Alveolar  C02  Tension  during  Breathing  in  a  Confined  Space,  357,  in 
Rarefied  Air,  360,  and  in  Apnea,  362. 

CHAPTER  XLI  I 

The  Control  of  Respiration    (Cont'd) ?,()(} 

The  Effect  of  Muscular  Exercise  on  the  Respiration,  .'l.jii. 

CHAPTER  XLIII 

The  Control  of  Respiration   (Cont'd) .",71 

Periodic  Breathing,  .".71  :  Types  of  Periodic  Breathing,  .".71  :  Causes  of  Periodic 
Breathing,  372. 

CHAPTER  XLIV 

Respiration  beyond  the  Lungs :::^ 

Transportation  of  Gases  by  the  Blood,  379;    Transportation   of  Oxygen,  379; 

Dissociation  Curve,  88";  Difference  between  Curves  of  Blood  and  Hemoglobin 
Solution,  383;  Rate  of  Dissociation,  ."86";  Dissociation  Constant.  38S. 

CHAPTER  XLV 

Respiration  beyond  the  Lungs   (Cont'd) .",00 

Means  by  Which  the    Blood   Carries  the  Gases,   390;   Oxygen   Requirement  of 

the  Tissues,  39.",;  Mechanism  by  Which  the  Demands  of  the  Tissues  for  Oxy- 
gen Are  Met.  397. 

CHAPTER   XJ.YI 

The  Physiology  op  Breathing  in  Compressed  Air  and  ix  Rarefied  Air     .    .    .  399 

Mountain  Sickness,  399;  Compressed  Air  Sickness  (Caisson  Disease).  102; 
Practical   Application  in   Treatment.  406. 

CHAPTER  XLVII 

TltE   ClRCULATORV    AND    RESPIRATOR?    CHANGES   ACCOMPANYING    MUSCULAR    EXERCISE   410 

Mechanical   Factor,  410;   Nervous   Factor,  412;    Hormone  Factor,  413. 


CONTENTS  XVH 

PART  V 
DIGESTION 

CHAPTEB    XIA'III  page 

General   Physiology  of  the  Digestive  Glands tl^ 

Microscopic  Changes  during  Activity,  H8;  Mechanism  of  Secretion,  120;  Other 
Changes  during  Activity,  421;  Control  of  Glandular  Activity,  122:  Nervous 
Control,  42::. 

CHAPTER   XLIX 

Physiology  of  the  Digestive  Glands  (Cont'd) 125 

Hormone  Control,  425;  Nervous  Control  of  the  Pancreas,  427. 

CHAPTER  L 

Physiology  of  the  Digestive  Glands  (Cont'd) 430 

Normal  Conditions  of  Secretion,  4:10;  Normal  Secretion  of  Sali\a,  4.".1  :  Secre-    . 
tion  of  Gastric  Juice,  4.">2  ;   The  Intestinal  Secretions,  441. 

CHAPTER  LI 

The  Mechanisms  of  Digestion 444 

Mastication,  444;  Deglutition,  445;  The  Cardiac  Sphincter,  448;  Y°miting, 
440. 

CHAPTER  LII 

The  Mechanisms  of  Digestion    (Cont'd) 451 

Movements  of  the  Stomach,  451  ;  Character  of  the  Movements,  451  ;  Effect 
of  the  Stomach  Movements  on  the  Food,  454;  Emptying  of  the  Stomach, 
45(5;  Control  of  the  Pyloric  Sphincter,  456;  Rate  of  Emptying  of  the  Stomach, 
45N ;  Influence  of  Pathologic  Conditions  on  the  Emptying,  450;  Gastroenter- 
ostomy, 461. 

CHAPTER  LIII 

The  Mechanisms  of  Digestion    (Cont'd) 46.°. 

Movements  of  the  Intestines,  463;  Movements  of  the  Small  Intestine,  46.'!; 
Movements  of  the  Large  Intestine,  468;  Effect  of  Clinical  Conditions  on  the 
Movements,  470. 

CHAPTER  LIV 

Hunger     and     Appetite 471 

Hunger  Contractions  of  Stomach,  471  ;  Remote  Effects  of  Hunger  Contrac- 
tions, 474;  Hunger  during  Starvation,  475;  Control  of  the  Hunger  Mechanism, 
476. 

CHAPTER  LV 

Biochemical    Processes    of    Digestion 4sl 

Digestion  in  the  Stomach,  481;  Functions  of  the  Hydrochloric  Acid,  4s2 ; 
Amount  ami  Source  of  the  Acid,  4^2;  Action  of  Pepsin,  4S5 ;  Clotting  of 
Milk  in  the  Stomach,  488. 


XVI 11  CONTEXTS 

CHAPTER  LVI  page 

Biochemical  Processes  of  Digestion    (Cont'd) 

Digestion   in  the   Intestines,   489;    Pancreatic   Digestion,   489;    The    ]'>il'\   492; 
Chemistry  of  Bile,  494. 

CHAPTER  LVII 

Bacterial  Digestion  in   the   Intestine 499 

Bacterial  Digestion  of  Protein,  501 ;  Botulism,  503. 


PART  VI 
THE  EXCRETION  OF  URINE 

CHAPTER  LVIII 

The  Excretion  of  Urine   (By  R.  G.  Pearce) 507 

Structure  of  Kidney,  507;  Mechanism  of  the  Excretion  of  Urine,  510;  Theories 
of  Renal  Function,  511;  Diuretics,  518;  Albuminuria,  519;  Influence  of  the 
Nervous  System  on  the  Secretion  of  Urine,  519. 

CHAPTER  LIX 

The  Amount,  Composition  and  Character  of  the  Urine  (By  R.  G.  Pearce)     .  521 
Amount,  522;   Specific  Gravity,  522;   Depression  of  Freezing  Point,  523;   Re- 
action, 524;   Solid  Constituents,  525. 


PART  VII 
METABOLISM 

CHAPTER  LX 

Metabolism 534 

Energy  Balance,  535;  Methods  for  Measuring  Energy  Output,  536;  Normal 
Values,  538 ;  Influence  of  Age  and  Sex,  541 ;  Influence  of  Diseases,  542 ; 
The  Material  Balance  of  the  Body,  543 ;  Methods  for  Measuring  Output,  543 ; 
Calculation  of  the  Results,  544. 

CHAPTER  LXI 
The  Carbon  Balance 547 

Respiratory  Quotient,  547;  Influence  of  Diet,  547;  Influence  of  Metabolism, 
549;  Magnitude  of  the  Respiratory  Exchange,  550;  Influence  of  Body  Tem- 
perature, 551. 

CHAPTER  LXII 

A  Clinical  Method  for  Determining  the  Respiratory  Exchange  in  Man  (By 

R.    G.    Pearce) 554 

The  Valves,  555;  Tissot  Spirometers,  556;  Douglas  Bag,  558;  Haldane  Gas- 
analysis  Apparatus,  559;  Calculations,  562. 


CONTENTS  XIX 

CHAPTEB   LXIH  page 

Starvation 566 

Excretion  oi  Nitrogen,  566;  Energy  Output,  568;  Nitrogenous  Metabolites,  568; 
Excretion  of  Purines,  569;  Excretion  of  Sulphur,  569;  Normal  Metabolism, 
570;  Nitrogenous  Equilibrium,  571  ;   Protein  Sparers,  571. 

CHAPTEB   L.XIV 

Nutrition  and  Growth 574 

The  Food  Factor  of  Growth,  574;  Relationship  of  Proteins  to  Growth  and 
Maintenance  of  Life,  574. 

CHAPTER  LXV 

Nutrition  and  Growth    (Cont'd) 583 

Relationship  of  Carbohydrates  and  Fats  to  Growth,  583;  Accessory  Food 
Factors,  or  Vitamines,  584;  Relationship  of  Inorganic  Salts,  580. 

CHAPTER  LXVI 

Dietetics 588 

Calorie  Requirements,  5S8;  The  Protein  Requirement,  590;  Accessory  Food 
Factors,  593;   Digestibility  and  Palatability,  593. 

CHAPTER  LXVII 

The  Metabolism   op  Protein1 595 

Introductory,  595;   Chemistry  of  Protein  and  of  the  Amino   Acids,   ."5 '. » 7 . 

CHAPTER  LXVIII 

The  Metabolism   of   Protein    (Cont'd)     .    , 606 

Amino  Acids  in  the  Blood  and  Tissues,  606;    Pate  of  the  Amino  Acids,  610. 

CHAPTER  LXIX 

The  Metabolism  of  Protein  (Cont'd) 613 

End  Products  of  Protein  Metabolism,  613;  Urea  and  Ammonia,  615;  In- 
fluence of  Acidosis  on  Ammonia-urea  Ratio,  616;  Influence  of  Liver  on  Am- 
monia-urea Ratio,  617;   Perfusion  of  Organs,  61S;   Clinical  Observations,   620. 

CHAPTER  LXX 

The  Metabolism  of  Protein  (Cont'd) 622 

Creatine  and  Creatinine,  622;  Essential  Chemical  Facts,  622;  Metabolism, 
624;  Influence  of  Food,  Age,  and  Sex,  624;  Origin  of  Creatine  and  Creatinine, 
626. 

CHAPTER  LXXI 

The  Metabolism  of  Protein  (Cont'd) 629 

Undetermined  Nitrogen  and  Detoxication  Compounds,  629;  Ethereal  Sulphates 
and  Glycuronates,  632. 

CHAPTER  LXXII 

Uric  Acid  and  the  Purine  Bodies 634 

Chemical  Nature  of  the  Purines,  634;  Chemical  Nature  of  the  Substances 
Containing  Purine  and  Pyrimidine  Bases,  637;  History  of  Nucleic  Acid  in  the 
Animal  Body,  638 ;  Balance  between  Intake  and  Output  of  Purine  Substances 
under  Various  Physiologic  and   Pathologic  Conditions,  641. 


XX  CONTENTS 

CHAPTEB  LXXII]  page 

Uric  Acid  and  the  Purine  Bodies  (Cont'd) 643 

Source  of  Endogenous  Purines,  643 ;  Influence  of  Various  Physiologic  Con- 
ditions, of  Drugs,  and  of  Disease  on  the  Endogenous  Uric-acid  Excretion, 
647;   Uric  Acid  of  Blood,  64S. 

CHAPTER  LXXIV 

Metabolism    of    the    Carbohydrates 652 

Capacity  of  the  Body  to  Assimilate  Carbohydrates,  652;  Assimilation  Limits, 
652 ;  Saturation  Limits,  654 ;  Digestion  and  Absorption,  656 ;  Sugar  Level  in 
the  Blood,  657;  Value  of  Blood  Examinations  in  Diagnosis  of  Diabetes,  659; 
Relationship   Between    Blood   Sugar  and  the  Occurrence   of  Glycosuria,  660. 

CHAPTER  LXXV 

Metabolism    of    the    Carbohydrates    (Cont'd) 662 

Fate  of  Absorbed  Glucose,  Gluconeogenesis,  662;  Storage  of  Sugar,  662; 
Sources  of  Glycogen,  662;   Gluconeogenesis  in   Normal  Animals,  667. 

CHAPTER  LXXVI 

Metabolism    of    the    Carbohydrates    (Cont'd) 669 

Fate  of  Glycogen,  669;  Regulation  of  the  Blood  Sugar  Level,  671;  Nerve 
Control  and  Experimental  Diabetes,  672;  Nervous  Diabetes  in  Man,  674; 
Hormone  Control  and  Permanent  Diabetes,  676;  Utilization  of  Glucose  in 
Tissues,  677;  Relation  of  the  Pancreas  to  Sugar  Metabolism,  678;  Diabetes 
and  the  Ductless  Glands,  67S;  Diabetic  Acidosis  or  Ketosis,  683;  Starvation 
Treatment,  684. 

CHAPTER  LXXVII 

Fat    Metabolism 686 

Chemistry  of  Fatty  Substances,  686 ;  Digestion  of  Fats,  690;  Absorption  of 
Fats,  691. 

CHAPTER  LXXVIII 

Fat  Metabolism    (Coxt'd) 696 

Fat  of  Blood,  696;  Methods  of  Determination,  690;  Variations  in  Bl 1   Pat, 

697;  Depot  Fat,  700;   Fat  in  the  Liver,  701. 

CHAPTER  LXXIX 

Fat  Metabolism    (Coxt'd) 707 

Production  of  Fatty  Acid  Out  of  Carbohydrate,  707;  Method  by  Which  the 
Fatty  Acid  is  Broken  Down,  709. 

CHAPTER  LXXX 

Control  of  Body  Temperature  axd  Fever 714 

Variations  in  Body  Temperature,  714;  Factors  in  Maintaining  the  Body  Tem- 
perature, 715;  Control  of  Temperature,  719;  Fever,  721;  Causes,  721;  Changes 
in  tlic  Body  during  Fever,  723;  Heat-iegulating  Center,  725:  Significance  of 
Fever,  726. 


CONTENTS  XXI 

PART  VII] 
THE   ENDOCRINE  ORGANS,  OR   DUCTLESS  GLANDS 

CHAPTER  LXXX1  page 

The  Endockine  Organs,  or  Ductless  Glands 729 

Methods  of  [Investigation;  730;  Adrenal  Gland,  7:il  ;  Cortex,  T.'M  ;  Medulla, 
7.'!2 ;   Adrenalectomy,  "•"..".:   Suprarenal   Extracts,  734;   Physiologic  Action,  7.".  t. 

CHAPTER  LXXXII 

Adrenal    Gland    (Cont'd) 738 

Variations  in  Physiologic  Activity,  738;  Assaying  the  Epinephrine  Content 
of  the  Gland,  738;  Epinephrine  Content  of  t lie  Blood,  7.'!!);  Autoinjecthm 
Method,  743;  Adrenalemia,  745;  Association  of  the  Adrenal  with  Other  En- 
docrine Organs,  746. 

CHAPTER  LXXXIII 

Thyroid  and  Parathyroid  Glands 740 

Structural  Relationship,  749;  Thyroid  Gland,  750;  Condition  of  Gland,  750; 
Experimental  Thyroidectomy,  7.52:  Disease  of  the  Thyroid,  '')'■);  Relation 
with  Other  Endocrine  Organs,  757;  Parathyroids,  758;  Experimental  Parathy- 
roidectomy, 758;  Relationship  with  Other  Endocrine  Organs,  761. 

CHAPTER  LXXXIV 

Pituitary    Body 762 

Structural  Relationships,  762;  Functions,  764;  Clinical  Characteristics,  771; 
Relationship  with  Other  Endocrine  Organs,  77.''. 

CHAPTER  LXXXV 

The  Pineal  Glaxd  axd  the  Goxads 776 

Pineal  Gland,  776;  Gonads  or  the  Generative  Organs,  776;  Generative  Glands 
of  the  Male,  776;  Generative  Organs  of  the  Female,  778. 


PART  IX 
THE  CENTRAL  NERVOUS  SYSTEM 

CHAPTER  LXXXVI 

The  Evolutiox  of  the  Nervous   System 781 

CHAPTER  LXXXVII 

Properties  or  Each  Part  of  the  Reflex  Arc 788 

Receptor,  788;   Epicritic  and  Protopathic  Receptors,  790;  Peculiarities  of  the 
Separate  Sensations,  791;  Temperature,  791;  Touch,  79.1;  Pain,  795. 

CHAPTER  LXXXVIII 

The  Properties  of  Each  Part  of  the  Reflex  Arc  (Cont'd) 796 

The  Nerve  Network,  796;  Network  on  Skin  Nerves,  796;   The  Synapsis,  797; 
The  Nerve  Cell,  799;  The  Intermediate  or  Internuncial  Neuron,  802. 


XX11  CONTENTS 

CHAPTER  LXXXIX 

Reflexes  of  the  Spinal  Animal  and  Spinal  Shock 803 

Spinal  Shock  in  Laboratory  Animals,  803;  Spinal  Shock  in  Man,  806;  Cause 
of  Spinal  Shock,  807. 

CHAPTER  XC 

Physiologic  Properties  of  the  Simple  Reflex  Arc 809 

Latent  Period,  809;  Grading-  of  Intensity,  809;  After-effect,  810;  Summation, 
810;  Irreversibility  of  the  Direction  of  Conduction,  810;  Refractory  Period, 
811;  Successive  Degeneration,  813. 

CHAPTER  XCT 

Reciprocal  Innervation 814 

Reciprocal  Inhibition,  814;   Action  of  Strychnine  and  Tetanus  Toxin,  819. 

CHAPTER  XCII 
Interaction    Among     Reflexes 821 

Integration  of  Allied  Reflexes,  S22 ;  Integration  of  Antagonistic  Reflexes, 
824;  Other  Factors  Which  Determine  Occupancy  of  Final  Common  Path,  824; 
Irradiation,  826. 

CHAPTER  XCIII 

The  Tendon  Jerks;  Sensory  Pathways  in  Spinal  Cord S28 

The  Tendon  Jerks,  828;  Afferent  Spinal  Pathways,  830. 

CHAPTER  XCIV 

Effects  of  Experimental  Lesions  of  Various  Parts  of  the  Nervous  System     .  835 
Anterior  Roots,  835;  Posterior  Roots,  S36;  Spinal  Cord,  and  Brain  Stem,  839; 
Medulla,   839;    Corpora   Quadrigemina,   840;    Removal   of   the   Cerebral   Hemi- 
spheres, S40. 

CHAPTER  XCV 

Cerebral  Localization S4:; 

Ablation  of  the  Motor  Centers,  843;  Stimulation  of  the  Motor  Centers,  844; 
Clinical  Observations,  849. 

CHAPTER  XCVI 

Cerebral    Localization     (Cont'd) 850 

Sensory  Centers,  850 ;   Sense  Centers,  851 ;  Association  Areas,  852. 

CHAPTER  XCVII 
Conditional  and  Unconditional  Reflexes 856 

CHAPTER  XCVIII 

Higher  Functions  of  t>jie  Cerebrum  in  Man;  Aphasia 860 

Psychopathological  Applications,   S62. 

CHAPTER  XCIX 

Functions   of   the   Cerebellum 865 

Localization  of  Function,  S67 ;  Circumscribed  Extirpation,  869;  Clinical  Ob- 
servations, 870. 


CONTENTS  \\iii 

CHAPTER  C 

The  Cerebellum  a.nd  the  Semicirculab  Canals;   Functional  Tests    ....  873 
Association    between   the    Eye   Movements   and    the   Semicircular   Canals,   875. 

CHAPTER  CI 
The   Autonomic   Nervous   System 877 

General  Plan  of  Construction,  877;  Thoracicolumbar  Outflow,  or  Sympathetic 
System  Proper,  8S0;  Bulbosacral  Outflow,  or  the  Parasympathetic  System,  882; 
Axon  Reflexes,  883;  Functions  of  Autonomic  Nerves,  884;  Afferent  Fibers  of 
the  Autonomic  System,  885. 


ILLUSTRATIONS 

Kid.  PAGE 

1.  Diagram  of  osmometer 5 

2.  Hematocrit  c 7 

3.  Plasmolysis  in  cells  from  Tradescantia   discolor 9 

I.  Apparatus  for  measurement  of  the  depression  of  freezing  poinl   of  solution     .  Jl 

5.  Diagram    of    conductivity    cells L8 

6.  Wheatstone  Bridge  for  the  measurement   of  electric  resistance IS 

7.  Diagram  to  show  type  of  electrodes  used   in   studying  electromotive   force     .     .  30 
!».  Chart    of    tints    as    used    in    colorimetric    measurement    of    I  lion    concentration. 

(Color  Plate.) .".4 

8.  Diagram  of  apparatus  for  the  measurement  of  the  H-ion  concentration     .     .  .'!1 

10.  Diagram  of  apparatus   for  -saturating  blood  and  plasma   with  expired  air     .  4."> 

11.  Van    Slyke's  apparatus   for   measuring   the   CCycombining   power  of   Mood    in 

blood  plasma 44. 

12.  Ultramicroscope    (slit    type)    for    the    examination    of    colloidal    solutions     .     .  52 

13.  To    show    diffusion    into    gelatin    of    a    crystalloid    stain,    and    the    nondiffusion 

of    a    colloid  stain 53 

14.  Diagram   from   W.   Ostwald  showing  the   relative  size   of   various  particles   and 

colloidal    dispersoids    compared    with    a    red    blood    corpuscle    and    an 

anthrax      bacillus 54 

15.  Capillary    analysis    of    colloids 5.6 

l(i.  Diagram  to  show  structure  of  gels 61 

17.  Diagram    to    illustrate    surface    tension 04 

18.  Traube's  stalagmometer '  ....  65 

lit.  Diagram  of  the  graphic  coagulometer 109 

20.  Coagulometer 110 

21.  Mercury  manometer  and  signal  magnet,  arranged  for  recording  the  mean  ar- 

terial blood  pressure  in  a  laboratory  experiment 1-4 

'2'2.  The  arterial  blood   pressure  recorded   with    a   mercury   manometer    (lower   trac- 
ing) along  with  a  tracing  of  the  respiratory  movement  of  the  thorax     .  125 
I'.'!.   Hiirthle's   spring   manometer 126 

24.  Arterial  pressure  recorded   by  a   spring  manometer ^-^ 

25.  Diagram    based    on    experiments    on    dogs    to    show    the    systolic,    diastolic    and 

mean  blood  pressures  at  different  parts  of  the  circulatory  system     .     .127 

26.  Apparatus  for  measuring  the  arterial  blood  pressure  in  man 129 

27.  Effect  of  cutting  the  vagus  nerve  on  the  arterial  blood  pressure 135 

28.  Effect   of    stimulating   the   peripheral    end    of   the   right   vagus   on    the    arterial 

blood    pressure        ' 

29.  Effect    of   stimulation   of  the  left   splanchnic   nerve  on    the   arterial   blood    pres- 

sure       

30.  The  effect  of  rapid  and  slow  hemorrhage  on  the  arterial  blood  pressure     .     .  138 

31.  Diagram  of  experiment   to  show   that   the  diastolic   pressure  depends  on  the 

elasticity   of   the   vessel   wall *™ 

.'!2.  Diagram    of    Wiggers'    optical     manometer I*6 

XXV 


XXVI  ILLUSTRATIONS 

FIG.  PAGE 

33.  Optical  records   of  intraventricular   pressure 147 

34.  Superimposed  pressure  curves  after  being  graduated 149 

35.  Von   Frank's  maximal   and    minimal   valve,   which   is   placed    in    the   course   of 

the   tube  between   heart   and   mercury   manometer 152 

36.  Diagram  to   show  the  positions  of   the  cardiac  valves 155 

37.  Diagram    showing   the   position    of    the    cardiac    chambers    and    valves    during 

presystole   and   during  the   sphymic   period 156 

38.  Electrophonograms   along   with   intraventricular   pressure    curves   from   three 

different     experiments        159 

39.  One    form    of   apparatus   for   recording   tracings   from    an    excised    heart     .     .  16.", 

40.  Volume  curve  of  ventricles  of  cat   (lower  curve)   in  a  heartdung  perfusion 

preparation 169 

41.  Heart  and  cardiac  nerves  of  hamulus  polyphemus 173 

42.  Heart-block  produced  by   applying  clamp 175 

43.  Tracing  of  contraction   of   ventricle,   showing   the   effect    of   the  local   appli- 

cation of  heat  to  the  auricle 175 

44.  Frog  heart  showing  the  position  of  the  first  and  second  ligatures  of  Stannius  176 

45.  Effects   of   stimuli   of   increasing   strength   on    skeletal   and   cardiac   muscle   to 

illustrate  the  "all  or  nothing"  principle  in  the  latter 177 

46.  The  effects  of  successive  stimuli  on  skeletal  and  cardiac  muscle  to  show  the 

prominence  of  the  staircase  phenomenon,  or  treppe,  in  the  latter     .     .  17S 

47.  The  effects  of  successive  stimuli  and  of  tetanizing  stimuli  on  skeletal  muscle 

and    cardiac    muscle 179 

48.  Myograms  of  frog's  ventricle,  showing  effect  of  excitation  Idv  break  induc- 

tion shocks  at  various  moments  of  the  cardiac  cycle 180 

49.  Heart   of   tortoise   as   suspended 183 

50.  Dissection  of  heart  to  show  auriculoventricular  bundle 184 

51.  Photograph  of  model  of  the  auriculoventricular  bundle  and  its  ramifications, 

constructed  »from   dissections  of  the  heart 184 

52.  Diagram   of  an  auricle  showing  the  arrangement  of  the  muscle  bands;   the 

concentration  point;   and  the  outline   of  the  node 186 

53.  Diagram   to   show   the   general   ramifications   of   the   conducting  tissue   in   the 

heart    of    the    mammal 186 

54.  Diagram  to  illustrate  the  development  and  spread  of  the  wave  of  negativity 

in  a  strip  of  muscle  (curarized  sartorius)  when  stimulated  at  the  end     .  188 

55.  Simultaneous  electrocardiograms  to  show  the  cause  for  extrinsic  deflections  190 

56.  Diagram  of  experiment  by  Lewis  showing  the  times  at  which  the  excitation 

wave  appeared  on  the  front  of  the  heart 194 

57.  Diagram  of  Chauveau's  dromograph 200 

58.  Diagram  to  show  principle  of  Pitot 's  tubes  for  measuring  velocity  pulse     .     .  201 

60.  Dudgeon  's   sphygmograph 201 

61.  Pulse  tracing   (sphygmogram)   taken  by  sphygmograph 202 

62.  Forms  of  apparatus    for  measurement   of  blood   velocities 207 

63.  Plethysmograph   for   recording   volume   changes   in    the  hand   and    forearm      .  210 

64.  Simultaneous    tracings   from    auricle    and    ventricle    of   turtle's   heart      .     .     .218 

65.  Effect  of  vagus  stimulation  on  heart  of  turtle ,  ' 

66.  Tracing    to    show    that    vagus    stimulation    may    diminish    transmission    from 

auricles  to   ventricles 


[LLUSTRATIONS  xxvn 

no.  PAGE 

67.  Tracing   to   show   thai    vagus   stimulation    may    facilitate    transmission   from 

auricles  to  ventricles 220 

68.  Diagram  to  show  the  innervation  of  the  bcarl   in  the  frog  or  turtle.     (Color 

Plate.) 224 

69.  Frog  heart  tracing  showing  the  action  of  nicotine 22G 

70.  Schematic   representation   of   the   innervation    of   the   heart    of   the    mammal. 

(Color  Plate.) 226 

71.  Tracings   showing  the  effects  on   the   heartbeat  of  the  frog  resulting  from 

stimulation    of   the    sympathetic    nerves   prior   to    their    union   with   the 
vagus   nerve 228 

72.  Roy  's  kidney  oncometer 230 

7."..  Fall  of  blood  pressure  from  excitation  of  tho  depressor  nerve 239 

74.  The  effect  of  strong  stimulation   (heat)   of  the  skin  of  the  foot  on  the  ar- 

terial  blood   pressure   and   respiratory   movements 241 

75.  Diagram  showing  the   probable  arrangements   of  the   vasomotor   reflexes     .  24i' 

76.  Aortic   blood   pressure,   showing   the   effect   of   posture 245 

77.  Tracing  to  show   the   effect  of  gravity   on   the   arterial  blood  pressure     .     .  245 

78.  The   effect   of  gravity   on  the   aortic  pressure   after   division   of  the   spinal 

cord  in  the  upper  dorsal  region 246 

79.  Schema  to  show  the  relations  of  the  Pacchionian  bodies  to  the  sinuses     .     .  248 

80.  Tracing  showing   simultaneous  records   of   the   arterial  blood   pressure,   the 

venous    pressure,    the    intracranial    pressure,    the   pressure    in    the   venous 

sinuses 251 

Bl.    Electrocardiographic   apparatus  as  made   by   the   Cambridge  Scientific   Ma- 
terials Co 260 

82.  Normal  electrocardiogram 261 

83.  Electrocardiogram  (dog)  taken  simultaneously  with  curves  from  auricle  and 

ventricle 262 

84.  Eccords  of  electrocardiogram  and   movement  of  ventricle  of  frog  showing 

that  when  the  apex  is  warmed  a  typical  T-wave  appears  in  place  of  a 

wave  in  the  opposite  direction   appearing  when  the  apex  is  cooled     .     .  264 

85.  Sinus   bradycardia 267 

86.  Auricular  extrasystole 267 

87.  Ventricular   extrasystoles   arising   in   the   right   ventricle 267 

88.  Ventricular   extrasystole   arising   in   the  left   ventricle 267 

89.  Paroxysmal  tachycardia 268 

90.  Auricular    fibrillation 268 

91.  Auricular    flutter 270 

92.  Delayed    conduction 270 

93    Partial    dissociation 271 

94.  Complete    dissociation 271 

95.  Polysphygmograph 274 

96.  Normal   jugular   tracing 274 

97.  Reduced  tracings  from  carotid,  aorta,  ventricle,  auricle  and  jugular,  to  show 

the  general  relationships   of  the   various  waves 275 

98.  Polysphygmograms    including    jugular,    apex    and    radial    tracings     ....  275 

99.  Delayed   conduction   time 277 

100.  Dropped   beats 277 

101.  Premature  beats   (extrasystoles)   ventricular  in  origin 278 


XXV111  ILLUSTRATIONS 

FIG-  PAGE 

102.  Paroxysmal    tachycardia '.  278 

103.  Auricular    flutter 279 

104.  Auricular    flutter 279 

105.  Auricular    fibrillation 280 

106.  Showing   the   appearance    of   the   blood    vessels    in    the    ears   of   a    rabbit    in 

a  state  of  deep  shock.      (Color  Plate.) 290 

107.  Diagram  showing  amounts  of  air  contained  by  the  lungs  in  various   phases 

of    ordinary    and    of    forced    respiration 301 

Ins.  Pneumograph :;n:; 

109.  Body   plethysmograph   for   recording   respiration 304 

110.  Effect   of  abdominal   and   chest   breathing  on   the  pulse  and   blood   pressure 

of    man 308 

111.  First  dorsal  vertebra,  sixth  dorsal  vertebra  ami  rib.     Axis  of  rotation  shown 

in    each    case 316 

112.  Lower  half   of   the    thorax   from    the    6th    dorsal    to    the   4th    vertebra,    seen 

from    the    front 318 

113.  Intercostal   muscles   of   5th   and   6th    spaces 310 

114.  Hamberger's  schema  to  demonstrate  the  functional  antagonism  of  internal 

and   external   intercostals 310 

115.  Schema     to     demonstrate     that     the     function     of     the     internal     interear- 

tilaginous     intercostals     is     identical     with     that     of     the     external    in- 
terosseous intercostals 320 

116.  Diagram   to   show   the   effect   of   high   and   low   positions   of   the   diaphragm 

on    the    costal   angle 322 

117.  Diagram    to    show    the   effect    of   clinical    displacements    of   the    diaphragm 

on    the    costal    angle 323 

118.  Diagram  to  show  cuts  required  for  isolation  of  the  phrenic   center     .     .     .  328 
110.  Diagram    to    show    certain    positions    in    the    medulla    and    upper    cervical 

cord,    where    sections    may    be    made    without    seriously    disturbing    the 
respirations 320 

120.  Diagram    to    show    where    cuts    are    made    to    isolate    the    chief    respiratory 

center    from    afferent    impulses 330 

121.  Diagram  showing  principle  for  measurement  of  the  tension   of  C02  in  blood   338 

122.  The  gas  analysis  pipette  for  the  microtonometer  shown  in  Fig.  123     .     .     .  339 

123.  Microtonometer,  to  be  inserted  into  a  blood  vessel 339 

121.  Apparatus  for  collection  of  a  sample  of  alveolar  air  by  Haldane's  method.     340 

125.  Fridericia's  apparatus  for  measuring  the  CO.  in  alveolar  air 341 

126.  Curves  to  show  the  relationship  between  the  O.  and  CO.  tensions  in   alveolar 

air  and  arterial  blood ".41 

127.  Same    as    Fig.    126,    except    that    in    this    case    the    tension    of    CO.    in    the 

alveolar    air    was    experimentally    altered 342 

128.  Arrangement  of  meters  and  connections  of  Pearee's   method   for   measure- 

ment of  CO.  of  alveolar  air  in  normal  subjects 346 

120.  Curve  showing  the  respiratory  response  to  CO,  in  the  decerebrate  cat      .     .  351 

130.  Tensions  of  O.  and  CO,  in  alveolar  air  at  different  altitudes 361 

131.  Curves   showing   variations   in    alveolar   gas   tensions   after    forced   breath- 

ing   for    two    minutes 364 

132.  Various   types   of  periodic    breathing 372 


ii.usTi;  \tio\s  wix 

no.  PAGE 

1.".."..  Quantitative   record   of   breathing   air   through    n    tube   260   cm.   long   and 

2   cm.    in    diameter .';7I 

134.  Barcroft'a   tonometer    for   determining    the   curve    of    absorption    of    oxvgen 

by   hemoglobin   or   blood 181 

135.  Barcroft'a   differential    blood    gas    manometer '-'^l 

130.  Barcrofl    blood   gas   manometer 382 

137.  Typical  dissociation  curve.     (Color  Plate.) 382 

138.  Average   dissociation   curves :'s' 

139.  Dissociation    curves    of    hemoglobin 385 

140.  Dissociation    curves   of   human    blood 386 

141.  Curves    showing    relative    rales    of    oxidation    and     reduction    of    blood    as 

influenced  by  temperature  and  by  tension  of  CO, 387 

Mi'.  Curve  of  COs  tension   in   blood 392 

lt.">.  (Alls  of   parotid   gland   showing  zymogen   granules 419 

1H.  Parotid  gland  of  rabbit  in  varying  states  of  activity  examined  in  fresh  stale  419 
14.").  Diagrammatic    representation    of    the    innervation    of    the    salivary    glands 

in  the  dog.      (Color  Plate.) 422 

146.  Pancreatic   acini   stained   with   hematoxylin 427 

147.  Three  preparations  of  pancreatic  acini  stained  by  eosinorange  toluidin  blue  128 
lis.   Diagram   showing   miniature   stomach    separated    from    the   main   stomach   by 

a  double  layer  of  mucous  membrane 434 

14J).  Typical    curve    of    secretion    of    gastric   juice    collected    in    5  minute    intervals 

on   mastication   of   palatable   food   for   20   minutes 4:!7 

150.  Cubic    centimeters    of    gastric    juice    secreted    after    diets    of    meat,    bread, 

and    milk 440 

151.  Digestive    power    of    the    juice,    as    measured    by    the    length    of    the    protein 

column   digested   in   Mett 's  tubes,   with  diets  of   flesh,   bread,   and  milk     .  441 

152.  Loop  of  intestine  after  tying  off  the  portions,  cutting  the  nerves  running  to 

the  middle  portion  and  returning  the  loop  to  the  abdomen  for  some  time  442 

153.  The   changes   which    take   place    in    the    position    of    the    root    of    the   tongue, 

the    soft    palate,    the  epiglottis    and    the    larynx    during    the    second 

stage    of    swallowing 4,1'' 

154.  Schematic    outline   of   the  stomach 452 

155.  Diagrams    of    outline    and  position    of    stomach    as    indicated    by    skiagrams 

taken    on    man    in   the    erect    position    at    intervals    after    swallowing   food 
impregnated    with    bismuth    subnitrate 452 

156.  Outlines  of  the  shadows  cast  by  the  stomach  at  intervals  of  an  hour  each 

after  feeding  a  cat   with   food   impregnated   with   bismuth   subnitrate     .     .  45.°. 

157.  Section    of    the    frozen    stomach    (rat)    some    time   after    feeding   with    food 

given    in    three    differently    colored    portions 455 

158.  Outlines   of  shadows   in   abdomen   obtained   by   exposure   to   x-rays   2   hours 

•after    feeding    with    food    containing    bismuth    subnitrate 458 

Lift.  Curves   to    show   the   average   aggregate    length    of   the   food    masses    in    the 

small    intestine    at    the    designated    intervals    after   feeding 459 

Pin.   Apparatus    for    recording    contractions    of    the    intestine 404 

161.  Diagrammatic  representation  of  the  process  of  segmentation  in  the  intestine  465 
102.  Intestinal     contractions     after     excision     of     the     abdominal     ganglia     and 

section    of    both    vagi 400 


XXX  [LLUSTRATIONS 

PIG.  PAGE 

163.  The    effect    of    excitation    of    both    splanchnic    nerves    on    the    intestinal 

contractions 4<">7 

164.  The     effect     of     stimulation     of     right     vagus     nerve     on     the     intestinal 

contractions 468 

165.  Diagram    of   time   it   takes   for   a   capsule    containing    bismuth    to    reach    the 

various  parts  of  the  large  intestine 4C>9 

166.  Diagram    of   method    for    recording    stomach    movements 472 

167.  "Tracing  of  the  tonus  rhythm  of  the  stomach  three  hours  after  a  meal     .     .    17.! 

168.  Tracings  from  the  stomach  during  the  culmination  of  a  period  of  vigorous 

gastric   hunger   contractions 473 

169.  Showing   augmentation    of   the   knee-jerk   during   the   marked   hunger   con- 

tractions     475 

170.  Diagram    of    the    uriniferous    tubules,    the    Jarteriea,    and    the     veins    of 

the   kidney 508 

171.  Cross  section  of  convoluted  tubules  from  kidney  of  rat 509 

172.  Diagram    of    blood    supply    of    Malpighian     corpuscle    and    of    convoluted 

tubules   in   amphibian   kidney 515 

173.  Nerve   supply   of   the   kidney 520 

174.  Respiration    calorimeter    of    the    Russell     Sage     Institute     of     Pathology, 

Bellevue  Hospital,  New  York 536 

175.  Chart  for  determining  surface  area  of  man  in  square  meters  from  weight 

in   kilograms  and  height   in   centimeters   according   to   formula     .     .     .  540 

176.  Diagram    of    Atwater-Benedict    respiration    calorimeter 543 

177.  Nose  clip,  face  mask,  and  mouthpiece 555 

178.  Diagram  of  respiratory  valves 556 

179.  The    Tissot  ■  spirometer 557 

180.  The   Douglas   bag  method   for   determining   the   respiratory    exchange     .     .  558 

181.  Haldane  gas  apparatus  and  Pearce  sampling  tube 559 

182.  Curve  constructed  from  data  obtained  from  a  man  who   fasted  for  thirty- 

one   days 567 

183.  Curves  of  growth  of  rats  on  basal  rations  plus  the  various  proteins  indicated  576 

184.  Curves  of  growth  of  rats  on  basal  rations  plus  the  proteins  indicated     .     .  577 

185.  Photographs    of    rats    of    same    brood    on    various    diets 579 

186.  Vividiffusion    apparatus    of    J.    J.    Abel 607 

187.  Curves  showing  the  amount  of  amino   nitrogen  taken  up  by   different  tis- 

sues after  the  cutaneous  injection  of  amino  acids 608 

188.  Curves  showing  the   concentration   of   amino-acid  nitrogen   in   the   blood   dur- 

ing fasting  and  protein  digestion 609 

189.  Curves   showing  the   percentage   of   glucose   in  blood    after   a   constant   injec- 

tion of  an  18  per  cent  solution  into  a  mesenteric   vein 658 

190.  Arrangement   of   apparatus   for  recording   contractions   of   a   uterine    strip, 

intestinal  strip,  or  ring,  etc "40 

191.  Tracing  showing  the   effect   of   epinephrine    on   the   intestinal    contractions 

and    on   the    arterial    blood   pressure ^1 

192.  Arrangement  of  apparatus  for  perfusion  of  the  vessels  of  a  brainless  frog    742 

193.  Microphotographs  of  thyroid  gland  of  dog "51 

194.  Cretin,   nineteen  years  old '54 

195.  Case    of    myxedema   before    and    after    treatment     . 755 

196.  Drawing  from  a  photograph  of  a  mesial  sagittal  section  through  the  pitui- 

tary gland  of  a  human  fetus '"•' 


ILLUSTRATIONS  x\\l 

in;.  PAG1 

l!»7.  Tracing    showing    the    action    of    pituitrin    on    the    uterine    contractions    and 

blood   pressure    in    a    dog 768 

L98.  Tracing  showing  the  constricting  action  of  pituitrin  on   the  bronchioles  and 

its  effect   on   blood   pressure    in    ;i   spinal    dog 7ii!> 

L99.  Showing  the  appearance  before  and  after  the  onsel  of  acromegalic  Bynvptoms  771 

200.  Hand  of  a   person   affected   with   acromegaly 772 

201.  Diagram    showing    gradual    evolution    of    nervous    system     in     sponge,    sen 

anemone,    and    earthworm 78:' 

202.  Diagram    of    nervous    system    of    segmented    invertebrate,    supraesophageal 

ganglion,  subeeophageal  ganglion,  esophagus  or  gullet 784 

203    Schema   of   simple    reflex   arc 785 

204.  Thermoesthesiometer 791 

205.  Cold  spots  and  heat  spots  of  an   area  of  skin  of  the  right  hand     ....  701! 
200.  Diagram   to   show   axon  reflex   of   sensory  nerve   fiber   of   skin 797 

207.  Arborization  of  collaterals  from   Hie   posterior  root   fibers  around  the   cells 

of   the    posterior    horn 798 

208.  Normal   cell   from  the   anterior   horn,   stained   to   show   Nissl's   granules     .     .  799 

209.  Part  of  an   anterior  cornual  cell  from  the   calf's  spinal   cord,   stained   to 

show    neurofibrils S00 

210.  Living   nerve   cells   examined   by   the   ultramicroscope 801 

211.  Tracing   from   the   hind  limb   of   a   spinal   dog   during   the   scratching   move- 

ments  produced   by   applying   stimuli   at   two    skin   points 812 

212.  Eecord  from  myograph  connected  with  the  extensor  muscle  of  the  knee     .  815 

213.  Diagram   showing   the   muscles   and   nerves   concerned   in   reciprocal    inner- 

vation               816 

214.  Eeciprocal   innervation 817 

215.  Sherrington's  diagram  illustrating  the  mechanism  of  reciprocal  innervation  81S 

216.  Diagram  showing  the  reflex  arcs  involved   in   the   scratch   reflex     ....  822 

217.  Showing  region  of  body  of  dog  from  which  the  scratch  reflex  can  be  elicited  823 

218.  Diagram   showing   the   segmental   arrangement   of   the   sensoiy   nerves     .     .  837 

219.  Outer    aspect    of    the    brain    of    the    chimpanzee 847 

220.  Three  sections  through   different   parts  of  the  cerebral  cortex 852 

221.  The  location  of  the  chief  motor  and  sensory  areas  on  the  outer  and  mesial 

aspects    of    the    human    brain 853 

222.  Footprints    after    destruction    of    the    cerebellum    in   a    dog 866 

223.  Diagrams  to  represent  respectively  a   ventral  view   of  the  left  half  and  a 

dorsal  view  of  the  right  half  of  the  human  cerebellum  illustrating  the 
scheme   of   subdivision    according   to   Bolk '    .  868 

224.  Schema  of  the  parts  of  the  mammalian  cerebellum  spread  out  in  one  plane     860 
225  and  226.  The  inferolateral  and  the  posterior  aspect  of  the  human  cerebellum 

indicating    certain    cerebellar    localizations    according    to    Barany     .     .     .  871 

227.  The    semicircular    canals    of    the    ear,    showing    their    arrangement    in    the 

three    planes    of    space 874 

228.  Diagram  illustrating  the   different  arrangements   of  the  internuncial  neurons 

of   the    voluntary   and   involuntary   nervous    systems 878 

22!'.  Diagram  of  the  sympathetic  nervous  system  to  be  used  along  with  Fig.  232. 

(Color    Plate.) 878 

230.  Diagram   showing   the   manner   of   connection   of   the   fibers   composing   the 

great  splanchnic  nerve.     (Color  Plate.) 878 


XXXII  ILLUSTRATIONS 

FIG-  PAGE 

231.  Diagram   showing   the   manner   in    which   a   preganglionic   fiber,   emanating 

from  the  spinal  nerve  by  the  white  ramus  communicans,  connects  in 
a  ganglion  of  the  sympathetic  chain  with  a  nerve  cell,  the  axon  of 
which  then  proceeds  as  the  postganglionic  fiber  by  way  of  the  gray 
ramus  communicans  back  to  the  spinal  nerve,  aloiii.'  which  it  travels 
to  the  periphery.     (Color  Plate.) 880 

232.  Diagram   showing   the   main   parts   of   the   autonomic    nervous   system    to   be 

used  along  with  Fig.  229.     (Color  Plate  ) 882 

2.'!:>.   Schematic   representation   of   the   involuntary  nervous   system.      (Color   Plate.)    881 


PHYSIOLOGY  AND  BIOCHEMISTRY 
IN  MODERN  MEDICINE 


PART  I 


THE  PHYSICOCHEMICAL  BASIS   OF  PHYSIOLOGICAL 

PROCESSES 


CHAPTER  I 
GENERAL  CONSIDERATIONS 

The  work  of  the  physiologist  consists,  in  Large  part,  in  ascertaining  to 
what  extent  the  known  laws  of  physics  and  chemistry  find  application 
in  explaining  the  phenomena  of  life.  He  gathers  from  the  vast  store- 
house of  physical  and  chemical  knowledge  whatever  is  of  value  in  the 
interpretation  of  the  various  mechanisms  that  work  together  to  com- 
pose the  living  machine,  and  having  added  to  this  knowledge  he  passes 
it  on  for  use  by  those  who  are  concerned  in  the  study  and  treatment  of 
disease. 

Many  of  the  most  important  steps  in  the  advance  of  physiologic 
knowledge  in  recent  years  have  depended  upon  the  discovery  of  some 
hitherto  unknown  physical  or  chemical  law,  or  upon  the  elaboration  of 
some  accurate  method  for  the  measurement  of  the  phenomena  upon 
which  these  or  previously  known  laws  depend.  The  discoveries  of 
van't  Hoff,  Arrhenius,  and  Ostwald  of  the  so-called  laws  of  solution 
were  soon  followed  by  important  observations  on  their  relationship  to 
the  movement  of  fluids  and  dissolved  substances  through  cell  mem- 
branes; the  discoveries  of  Hardy,  Willard  Gibbs,  etc.,  of  the  behavior  of 
colloids  and  of  the  phenomena  of  surface  tension  found  application  in 
explaining  many  hitherto  inexplicable  peculiarities  in  the  activities  of 
ferments:  the  discovery  by  Nernst,  etc.,  of  methods  for  the  measurement 
of  the  electro-motive  force  of  dissolved  substances  was  applied  to  de- 
termine  the   actual    reaction   or   hvdrogen-ion    concentration    of   animal 


2  PHYSICOCHEMICAL    BASIS    OF   PHYSIOLOGICAL   PROCESSES 

fluids,  and  to  explain  the  generation  of  the  electric  currents  which  ac- 
company muscular,  nervous,  and  glandular  activity. 

It  would  be  out  of  place  here  to  devote  much  space  to  a  detailed  ac- 
count of  such  matters.  They  belong  more  properly  in  the  domain  of 
general  than  in  that  of  human  physiology.  General  physiology  is  con- 
cerned with  the  study  of  the  essential  nature  of  the  vital  processes; 
whereas  human  physiology  is  merely  a  branch  of  the  subject  in  which 
special  attention  is  devoted  to  the  application  of  the  truths  of  general 
physiology  to  the  working  of  the  human  machine.  For  the  physician 
and  surgeon  a  knowledge  of  human  physiology  is  as  essential  as  is  a 
knowledge  of  the  construction  of  a  piece  of  machinery  for  the  engineer 
who  attempts  its  repair,  but  obviously  to  acquire  this  knowledge  the 
fundamental  principles  of  general  physiology  must  first  of  all  be  under- 
stood. For  these  reasons  the  introductory  chapters  are  devoted  to  a 
brief  review  of  the  most  important  of  the  physicochemical  principles 
upon  which  the  working  of  the  cell  depends. 

From  the  viewpoint  of  the  physical  chemist  the  cell  consists  of  an 
envelope  of  more  or  less  permeable  material  inclosing  a  dilute  solution 
of  crystalline  substances  in  which  colloid  matter  is  suspended.  It  con- 
tains, in  other  words,  a  solution  of  crystalloids  and  colloids,  in  which 
these  are  in  a  state  of  equilibrium  with  each  other.  This  equilibrium  is 
readily  altered  by  various  influences  that  may  act  on  the  cell,  and  the 
resulting  changes  manifest  themselves  outwardly  by  alterations  in  the 
shape  and  volume  of  the  cell — growth  and motion ;  by  the  extrusion  of 
some  of  its  contents — secretion;  or  by  the  propagation  to  other  parts  of 
the  cell,  or  its  processes,  of  the  state  of  disturbed  equilibrium — nervous 
impulse.  Besides  the  activities  that  are  dependent  upon  physicochem- 
ical changes,  purely  chemical  processes  go  on  in  the  cell.  Many  of 
these  consist  in  the  breakdown  and  oxidation  of  complex  unstable  organic 
molecules,  a  process  identical  with  that  occurring  in  combustion  outside 
the  cell.  Others  involve  the  building  up,  stage  by  stage,  of  complex 
substances  out  of  the  elements  or  out  of  simpler  molecules.  Chemical 
transformations  occur  in  the  cell  which,  in  the  chemical  laboratory,  re- 
quire the  most  powerful  reagents  and  physicochemical  forces,  either  the 
strongest  of  acids,  alkalies,  oxidizing  agents,  etc,  or  extreme  degrees 
of  heat,  electrical  energy,  etc.  But  this  is  not  all,  for  in  the  cell  these 
chemical  transformations  are  capable  of  being  guided  to  a  very  remark- 
able degree  of  nicety  so  as  to  produce  intermediate  products  that  are 
used  for  some  special  purpose  either  by  the  cell  that  produced  them  or, 
after  transportation  by  the  blood,  etc.,  by  cells  in  other  parts  of  the 
organism. 

It  is  customary  to  speak  of  the  cell  as  a  chemical  laboratory,  but  it 


LAWS  01'  SOLUTION 

is  more  than  this;  it  is  a  Laboratory  furnished  nol  only  with  the  equip- 
ment of  the  chemist  but  directed  in  the  harmonious  operation  of  its 
many  activities  by  a  guiding  hand  which  Ear  surpasses  anything  known 
to  111,111.  Chemical  transformations  that  require  for  their  accomplishment 
the  greatest  skill  proceed  without  apparent  difficulty  in  the  cell.  To 
what  are  these  changes  due?  What  is  the  nature  of  the  chemical  rea- 
gents and  forces,  and  what  is  the  directive  influence  that  guides  them 
in  their  varied  activities?  To  these,  which  are  among  the  great  ques- 
tions of  general  physiology,  the  reply  may  be  given  that  the  reagents 
are  the  ferments  or  enzymes,  and  that  the  directive  influence  operates 
through  the  susceptibility  of  enzymic  activities  to  changes  in  the  envi- 
ronment in  which  the  enzymes  are  acting.  In  many  cases  these  changes 
can  be  explained  on  a  physicochemical  basis  as  dependent  upon  the 
known  laws  of  mass  action  or  surface  tension;  in  other  cases  they  de- 
pend on  purely  chemical  changes  in  the  cell  contents,  such  as  changes 
in  reaction  or  the  accumulation  of  chemical  substances  that  act  like 
poisons  on  the  enzyme.  But  there  are  still  others  that  appear  to  depend 
on  influences  which  as  yet  are  quite  unknown  to  the  physical  chemist, 
such  as  the  changes  in  cell  activity  that  can  be  brought  about  by  the 
nerve  impulse. 

These  preliminary  remarks  will  serve  to  indicate  the  problems  with 
which  Ave  must  first  occupy  our  attention.  They  concern  the  physico- 
chemical  nature  of  saline  solutions  and  of  colloids,  and  the  general  na- 
ture of  enzyme  action.  The  knoAvledge  which  Ave  acquire  will  be  found 
to  be  of  A'alue,  not  only  because  it  will  help  us  to  understand  the  nature 
of  the  Avorkings  of  the  normal  healthy  cell,  but  because,  here  and  there, 
it  will  indicate  possible  causes  for  derangement  in  cellular  function  and 
suggest  rational  means  by  which  Ave  may  attempt  to  rectify  the  fault. 

THE   PHYSICOCHEMICAL   LAWS   OF   SOLUTION 

The  Gas  Laws 

Three  fundamental  principles  of  general  chemistry  serve  as  the  basis 
for  an  understanding  of  the  nature  of  solutions.  The  first  is  that  if 
Ave  take  a  quantity  of  any  gas  equal  to  its  molecular  Aveight  in  grams 
(called  a  gram-molecule  or  for  sake  of  brevity  a  mol),  it  will  occupy  ex- 
actly 22.4  liters  at  standard  temperature  and  pressure;  the  second  is 
that,  as  Ave  compress  a  gas,  its  pressure  will  increase  in  exactly  the 
same  proportion  as  the  Arolume  diminishes  (the  A'olume  of  a  gas  is  inA-ersely 
proportional  to  its  pressure) ;  the  third  is  that  all  gases  expand  by  1/273 


4  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

part  of  their  volume  at  0°  C.  for  every  degree  C.  that  their  temperature 
is  raised.* 

The  pressure  of  a  gas  is  measured  by  connecting  a  pressure  gauge  or 
manometer  with  the  vessel  which  contains  the  gas.  Now,  it  is  plain 
that  if  the  22.4  liters,  -which  is  the  volume  occupied  by  a  gram-molecular 
quantity,  Ave  re  compressed  so  as  to  occupy  a  Arolume  of  1  liter,  its  pressure 
Avould  be  22.4  times  that  of  1  atmosphere,  or  22.4  x  760  mm.  Hg — the 
temperature  remaining  constant.  Under  these  conditions  Ave  must  im- 
agine that  the  molecules  of  gas  are  croAvded  together  by  the  compression, 
and  if  Ave  further  conceiA'e  of  these  molecules  as  being  in  constant  mo- 
tion, then  Ave  can  understand  why  the  pressure  should  increase  just  in 
proportion  as  Ave  confine  the  space  in  Avhich  they  can  move. 

One  other  property  of  gases  must  be  borne  in  mind — namely,  their 
tendency  to  diffuse  from  places  Avhere  the  pressure  is  high  to  places 
Avhere  it  is  Ioav  until  the  pressure  is  the  same  throughout. 

OSMOTIC  PRESSURE 

These  fundamental  facts  regarding  the  behavior  of  gases  suggested 
to  A'an't  Hoff  the  hypothesis  that  molecules  of  dissolved  substances  must 
behave  in  a  similar  manner  to  those  of  gases.  To  put  this  hypothesis  to 
the  test,  it  is  necessary  that  Ave  have  some  method  for  measuring  the 
pressure  of  dissolved  molecules.  We  can  not,  as  in  the  case  of  a  gas, 
use  an  ordinary  manometer,  for  this  Avould  measure  only  the  pressure 
of  the  solvent  on  the  Avails  of  its  container  and  Avould  tell  us  nothing  of 
the  pressure  of  the  dissolved  molecules.  AVe  must  use  some  filter  or 
membrane  that  will  allow  the  molecules  of  the  solvent  but  not  those  of 
the  dissolved  substance  to  pass  through  it.  It  is  evident  that  if  such  a 
filter  is  placed,  for  example,  betAveen  a  solution  of  sugar  in  Avater  and 
Avater  alone,  the  molecules  of  the  latter  will  diffuse  into  the  solution 
until  this  has  become  so  diluted  that  the  pressure  of  the  dissolved  mol- 
ecules is  equal  on  both  sides  of  the  membrane.  Such  a  membrane  is 
called  semipermeable;  the  diffusion  of  molecules  through  it  is  called 
osmosis,  and  the  pressure  which  is  generated,  the  osmotic  pressure.  If 
Ave  prevent  the  Avater  molecules  from  actually  diffusing  by  opposing 
a  pressure  Avhich  is  equal  to  that  Avith  Avhich  they  tend  to  diffuse  through 
the  membrane,  Ave  can  tell  the  magnitude  of  the  osmotic  pressure  (Fig.  1"). 

In  applying  these  facts  to  test  the  hypothesis  that  molecules  in  solution 


*This  implies  that  at  -273°  C.  the  gas  would  occupy  no  volume.  Before  this  temperature  is 
reached,  however,  the  liquefaction  of  the  gas  sets  in.  The  temperature  -273°  C.  is  known  as  absolute 
zero.  An  observed  temperature  pl'ls  -73°  is  called  the  absolute  temperature.  Another  way  of  stat- 
ing the  above  law  is  therefore  that  the  volume  is  directly  proportional  to  the  absolute  temperature. 
At  273"  C.  the  volume  of  a  gas  at  0°  C.  would  be  doubled,  or  if  expansion  were  prevented  the 
pressure  would  be  doubled. 


LAWS  OF  SOLUTION  ■) 

obey  the  same  laws  as  those  in  gaseous  form,  we  must  employ  a  semi- 
permeable membrane  which  is  rigid  enough  to  withstand  the  pressure 
and  which  tonus  part  of  the  walls  of  a  closed  vessel  connected  with  a 
manometer.  If  we  place  in  such  an  osmometer  a  solution  containing  the 
molecular  weight  in  grams  of  some  substance  dissolved  in  one  liter  of 
solvent,  a  so-called  gram-molecular  solution,  it  is  obvious  that,  if  the 
gas  laws  are  to  apply,  the  osmotic  pressure  should  equal  that  of  22.4 
liters  of  a  gas  compressed  to  the  volume  of  one  liter;  in  other  -words, 
it  should  equal  22.4x7(50  mm.  Eg.  Although  there  are  very  consider- 
able technical  difficulties  in  making  a  semipermeable  membrane  that  is 
strong  enough  to  withstand  such  a  pressure,  yet  this  has  been  accom- 


M  I 


W 


Fig.  1. — Diagram  of  osmometer.  The  cylindrical  vessel  (O),  with  a  bottom  of  unglazed 
clay,  the  pores  of  which  are  filled  with  a  precipitate  of  copper  ferrocyanide  to  form  a  semi- 
permeable membrane,  is  suspended  in  an  outer  vessel,  and  is  closed  above  by  a  tightly  fitting 
stopper  [pierced  by  a  tube  leading  to  a  manometer  (M).  O  contains  a  strong  solution  of  cane 
sugar,  and  li'  contains  water.  The  water  molecules  tend  to  pass  through  the  semipermeable 
membrane  into  the  cane  sugar  solution,  and  since  the  cane  sugar  molecules  can  not  pass  in 
the  opposite  direction,  the  pressure  in  O  rises  and  is  recorded  in  .1/.  This  equals  the  osmotic 
pressure. 


plished,  and  the  fundamental  principle  has  therefore  been  firmly  estab- 
lished that  substances  in  solution  obey  the  same  laws  as  gases. 

Further  proof  that  the  gas  laws  apply  to  solutions  has  been  secured  by 
showing  that  the  osmotic  pressure  (of  a  dilute  solution)  is  directly  pro- 
portional to  the  concentration  of  the  dissolved  substance  (the  solute) 
and  to  the  absolute  temperature.  It  also  obeys  the  law  of  partial  pres- 
sures, which  states  that  the  total  pressure  exerted  by  a  mixture  (of  gases 
or  dissolved  molecules)  is  the  sum  of  the  pressures  which  each  constit- 
uent of  the  mixture  would  exert  were  it  alone  present  in  the  space 
occupied  by  the  mixture. 


b  PHYSICOCHEMICAL    BASIS   OF   PHYSIOLOGICAL   PROCESSES 

Since  the  osmotic  pressure  is  analogous  to  the  pressure  of  a  gas  and 
is  therefore  proportional  to  the  molecular  concentration  (i.  e.,  number 
of  molecules  in  unit  space),  it  follows  that  a  semipermeable  membrane 
can  be  used  to  determine  the  relative  concentration  of  two  solutions  of 
the  same  substance.  When  a  watery  solution  of  some  substance  is 
placed  in  an  osmometer  that  is  surrounded  by  a  similar  but  more  dilute 
solution,  water  molecules  will  diffuse  into  the  osmometer  until  the  pres- 
sure is  equal  on  the  two  sides  of  the  semipermeable  membrane;  that  is, 
the  water  will  pass  from  the  solution  having  a  lower  osmotic  pressure 
into  the  solution  having  the  higher  pressure.  When  two  solutions  have 
the  same  osmotic  pressure,  they  are  said  to  be  isotonic;  when  that  of  one 
is  greater  than  that  of  the  other,  it  is  hypertonic;  and  when  less,  hypotonic. 

Biological  Methods  for  Measuring  Osmotic  Pressure 

A  practical  biological  application  of  these  principles  can  very  readily 
be  made  if,  instead  of  a  rigid  semipermeable  membrane  such  as  that 
figured  in  the  diagram,  we  employ  one  that  is  extensible  and  takes  the 
form  of  a  closed  sac ;  then  as  diffusion  of  water  occurs  the  sac  will  either 
distend  when  it  contains  a  stronger  solution  than  that  outside,  or  shrivel 
or  crenate  when  the  reverse  conditions  obtain.  Many  animal  and  veg- 
etable protoplasmic  membranes  are  semipermeable,  including  the  en- 
velope of  red  blood  corpuscles.  Thus,  if  we  examine  blood  corpuscles 
under  the  microscope  and  add  to  them  a  saline  solution  of  higher  os- 
motic pressure  than  blood  serum,  they  will  visibly  diminish  in  size  and 
become  irregular  in  shape;  whereas  if  the  solution  is  of  lower  osmotic 
pressure,  they  will  distend.  If  no  change  occurs,  the  osmotic  pressure  of 
the  cell  contents  must  equal  that  of  the  saline  solution  in  which  the  cells 
are  immersed,  from  which  it  is  clear  that  we  can  readily  determine  the 
magnitude  of  the  osmotic  pressure  if  Ave  know  the  strength  of  the 
saline  solution. 

Instead  of  measuring  the  individual  cells  under  the  microscope,  we  can 
measure  the  space  they  occupy  in  the  fluid  in  which  they  are  suspended. 
For  this  purpose  a  portion  of  the  suspension  is  placed  in  a  graduated 
tube  of  narrow  bore,  which  is  rotated  in  a  horizontal  position  by  a  cen- 
trifuge after  being  closed  at  one  end.  The  graduation  at  which  the 
upper  edge  of  the  column  of  cells  stands  after  centrifuging  is  a  measure 
of  the  relative  amount  of  cells  and  fluid  in  the  suspension.  Having 
found  this  value  for  cells  suspended  in  an  isotonic  solution,  as  for  blood 
corpuscles  in  blood  serum,  Ave  may  then  proceed  to  ascertain  it  for  the 
same  cells  suspended  in  an  unknoAvn  solution;  if  Ave  find  that  the  cells 
occupy  a  greater  A^olume,  the  saline  solution  must  have  an  osmotic  pres- 


LAWS    OF  SOLUTION  7 

sure  that  is  lower  than  that  of  serum  in  approximate  proportion  to  the 
readings  on  the  tube  in  the  two  cases,  and  vice  versa. 

The  above  apparatus,  called  a  hematocritc  (Fig.  2)  lias  been  very  ex- 
tensively used  in  the  collection  of  data  concerning  the  relative  osmotic 
pressures  of  different  physiologic  fluids. 

Hemolysis 

Another  way  for  determining  the  relative  osmotic  pressure  of  dif- 
ferent solutions  consists  in  placing  equal  amounts  (a  few  drops)  of 
blood  in  a  series  of  test  tubes  containing  solutions  of  different  strengths, 
and  after  allowing  the  tubes  to  stand  for  some  time,  noting  in  which  of 
them  hiking  of  the  blood  corpuscles  occurs.  In  solutions  Avhich  are 
isotonic  or  hypertonic  with  the  contents  of  the  corpuscles,  the  latter 
will  settle  to  the  bottom  of  the  tube  and  the  supernatant  fluid  will  be 
untinted  with  hemoglobin,  but  in  solutions  which  are  distinctly  hypotonic, 
the  sediment  will  be  less  distinct  and  the  supernatant  fluid  red. 


Fig.  2. — Hematocrite.  The  graduated  glass  tubes  are  hlled  with  the  two  specimens  of 
blood,  or  corpuscular  suspension,  and  then  rotated  rapidly  by  a  centrifuge.  The  relative  heights 
at  which  the  corpuscular  sediment  stands  in  the  two  tubes  is  proportional  to  the  osmotic 
pressures    of    the    fluid    in    which    the    corpuscles    are.  suspended. 

By  noting  (1)  the  lowest  concentration  (percentage  composition)  of 
the  solutions  in  which  the  corpuscles  sink  to  the  bottom  and  leave  the 
supernatant  fluid  colorless,  and  (2)  the  highest  concentration  in  which 
the  corpuscles  when  they  settle  leave  the  supernatant  fluid  red,  we  can 
determine  the  limiting  concentrations  for  solutions  of  different  sub- 
stances. Thus,  with  bullock's  blood  the  folloAving  results  were  obtained 
(Hamburger) : 


SUBSTAXCK 


Percentage  Strength  of  tSoLUTic-N  in  Which  : 
I  II 

SUPERNATANT  FLUID  SUPERNATANT  FLUID 

WAS  COLORLESS  AVAS  RFD 


KN03 

1.04 

NaCl 

0.60 

K..S04 

1.16 

C,,H„0M   (Cane  sugar) 

0.29 

CHnCOOH    (Pot.  acetate) 

1.07 

MgS04 .  7H20 

3.52 

CaCL, 

0.S5 

0.9(5 
0.5(3 
1.06 
5.6.3 
1.00 
3.26 
0.79 


8  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

The  mean  of  these  limiting  concentrations  is  the  critical  concentration 
and  indicates  the  strength  of  each  solution  that  can  be  added  to  blood 
without  causing  any  damage  to  the  corpuscles.  This  critical  concen- 
tration is  not,  as  might  at  first  sight  be  imagined,  the  same  as  that 
which  is  isotonic  with  the  contents  of  the  corpuscles,  but  distinctly 
below  it.  The  reason  for  this  becomes  apparent  if  we  observe  the  be- 
havior of  corpuscles  suspended  in  an  isotonic  solution  which  is  then 
gradually  diluted.  As  dilution  proceeds,  the  corpuscles  distend,  until  at 
last  their  envelopes  burst  and  the  hemoglobin  is  discharged.  The  lim- 
iting concentrations  of  a  given  salt  vary  for  different  corpuscles;  thus, 
the  concentration  of  sodium  chloride  solution  that  just  causes  hiking  of 
frog's  blood  corpuscles  is  0.21  per  cent,  of  human  blood  0.47  per  cent, 
and  of  horse  blood  0.68  per  cent.  It  is  the  strength  of  the  corpuscular 
envelope  rather  than  variations  in  the  osmotic  pressure  of  the  contents 
that  is  responsible  for  these  differences. 

The  above  described  method  of  hemolysis,  as  it  is  called,  can  not  be 
used  for  comparisons  of  osmotic  pressure  in  cases  in  which  the  solution 
contains  substances  which  alter  the  permeability  of  the  corpuscular 
envelop;  for  example,  it  can  not  be  used  when  urea,  or  ammonium 
salts,  or  certain  toxic  bodies  are  present.  This  very  fact  is,  however, 
put  to  a  useful  purpose  in  ascertaining  whether  a  given  substance  does 
have  a  damaging  influence  on  the  corpuscular  envelope  by  finding  whether 
hemolysis  occurs  when  we  suspend  the  corpuscles  in  a  solution  that  is 
isotonic  with  the  corpuscular  contents.  We  can  further  determine  the 
degree  of  this  toxic  influence  J>y  estimating  by  color  comparisons 
(colorimetry)  the  amount  of  hemoglobin  that  has  diffused  out  of  the 
corpuscles. 

Plasmolysis 

An  analogous  method  for  determining  osmotic  pressure  is  that  of 
plasmolysis,  in  which  the  behavior  of  certain  plant  cells  is  observed 
microscopically  while  they  are  in  contact  with  solutions  of  different 
strengths.  When  the  surrounding  solution  is  isotonic  with  the  cell 
contents,  the  latter  fill  the  cell  and  extend  up  to  the  more  or  less  rigid 
cell  wall  LI  in  Pig.  3)  ;  but  when  the  solution  is  hypotonic,  the  cell 
contents  become  detached  from  the  cell  wall  at  one  or  more  places — 
plasmolysis  (B  and  C).  The  semipermeable  membrane  in  this  case  is 
therefore  not  the  cell  wall  but  the  layer  of  protoplasm  on  the  surface 
of  the  cell  contents.  The  method  can  be  used  only  for  detecting  solu- 
tions that  are  hypertonic,  for  with  those  that  are  hypotonic  the  cells 
merely  become  turgid  and  exert  more  pressure  on  the  more  or  less 
rigid  cell  wall.     Many  of  the  conclusions  that  have  been  drawn  from 


LAWS  OF  SOLUTION  !) 

results  obtained  by  the  plasmolytic  method  have  recently  been  called  in 
question,  because  no  regard  1ms  been  taken  of  the  power  of  the  colloids 
of  the  eelJ  to  adsorb  (imbibe)  water  (see  page  G2). 

The  methods  of  hemolysis  and  plasmolysis  have  been  used  for  the 
investigation  of  many  problems  in  medicine.  In  the  case  of  certain 
toxic  fluids,  such  as  snake  venom,  tetanus  toxin,  etc.,  determination  of 
the  hemolytic  power  has  proved  of  value  in  roughly  assaying  the  dam- 
aging influence  on  other  cells  than  blood  corpuscles.  Studies  in  hemol- 
ysis have  also  been  especially  valuable  in  working  out  the  mechanism 
by  which  cellular  toxins  in  general  develop  their  action,  and  the  conditions 
under  which  this  action  may  be  counteracted,  as  by  the  development  of 


Fig.  3. — -To  show  plasmolysis  in  cells  from  Tradescantia  discolor.  A.  normal  cell;  B, 
plasmolysis  in  0.22  M.  cane  sugar;  C,  pronounced  plasmolysis  in  1.0  M.  KN03;  h,  the  cell 
wall;    p,    the    protoplasm.      (After    De    Vries.) 

antibodies.  Furthermore,  any  solution  that  is  to  be  injected  into  the 
animal  body,  either  intravenously  or  subcutaneously,  should  first  of  all 
be  tested  by  the  above  methods  in  order  to  find  out  whether  it  is  isotonic 
with  the  body  fluids.  If  a  hypertonic  solution  is  injected,  it  will  result 
in  the  abstraction  of  water  from  the  tissue  cells,  whereas  a  hypotonic 
solution  will  cause  the  water  content  of  these  to  increase.  Advantage 
has  recently  been  taken  of  this  water-abstracting  effect  of  hypertonic 
solutions  in  the  treatment  of  wounds.  By  constantly  bathing  them  with 
strong  saline  solutions,  an  outflow  of  water  is  set  up  from  the  tissue 
cells  that  border  on  the  wound,  and  this  tends  to  bring  to  the  focus  of 
infection  the  defensive  substances  that  are  present  in  animal  fluids. 


CHAPTER  II 
OSMOTIC  PRESSURE  (Cont'd) 

Measurement  by  Depression  of  Freezing-  Point 

The  limitations  in  the  use  of  the  plasmolytic  and  hemolytic  methods 
in  the  precise  measurement  of  the  osmotic  pressure  of  the  body  fluids 
have  rendered  it  necessary  to  find  some  physical  method  that  will  be 
generally  applicable.  Because  of  technical  difficulties,  it  is  impracticable 
to  measure  the  pressure  directly  by  employing  an  osmometer,  so  that 
some  indirect  method,  depending  on  a  readily  measurable  physical  prop- 
erty which  varies  in  proportion  to  the  osmotic  pressure  of  the  dissolved 
substances,  must  be  used.  Fortunately,  one  such  exists  in  the  property 
which  dissolved  substances  have  in  lowering  the  temperature  at  which 
the  pure  solvent  solidifies;  the  freezing  point  of  pure  water,  for  example, 
is  lowered  when  substances  are  dissolved  in  it,  and  the  extent  of  this 
lowering,  with  certain  reservations  which  will  be  explained  later  (page 
16),  is  proportional  to  the  molecular  concentration  of  the  solution  and 
independent  of  the  chemical  nature  of  the  substance  dissolved.  This 
lowering  of  temperature  is  designated  by  the  Greek  letter  A,  and  to 
measure  it  a  thermometer  is  used  Avhich  is  not  only  extremely  sensitive 
but  in  which  the  level  of  the  mercury  column  can  be  adjusted  so  that  it 
stands  at  a  convenient  level  on  the  scale  corresponding  to  the  freezing 
point  of  whatever  solvent  was  used  in  making  the  solution  under  investi- 
gation (Beckmann's  thermometer)  (Fig.  4).  The  exact  position  on 
the  scale  of  this  thermometer  at  which  the  pure  solvent  freezes  having 
been  ascertained,  the  observation  is  repeated  with  the  solution  whose 
osmotic  pressure  is  to  be  determined. 

A  gram-molecular  solution  in  water  (having  therefore  an  osmotic  pres- 
sure of  170,240  mm.  Hg)  has  a  freezing  point  that  is  1.86°  C.  lower  than 
that  of  pure  water.  This  is  known  as  the  "freezing  point  constant," 
and  it  varies  for  different  solvents,  being  3.9  for  acetic  acid  and  4.9 
for  benzene.  If  an  unknown  watery  solution  is  found  to  have  a  freez- 
ing point  that  is  A0  C.  lower  than  that  of  water,  its  osmotic  pressure 

:11           .  A  x  17.024 
will  equal  — —^ mm.  Hg. 

10 


osmotic    i'i;i:ssi:i;i: 


11 


The  depression  of  the  freezing  points  produced  by  the  various  body 
fluids  has  been  compared,  the  objects  in  view  being  to  see  whether 
osmotic  pressure  is  a  property  which  changes  under  different  physiologic 

and  pathologic  conditions,  and  to  find  out  by  comparison  of  the  osmotic 
pressures  of  the  Quids  in  contact  with  a  membrane,  whether  physical 
forces  alone  can  be  held  responsible  for  the  transference  of  substances 
through  it  from  one  fluid  to  the  other. 

The  Role  of  Osmosis,  Diffusion,  and  Allied  Processes  in  Physiologic 

Mechanisms 

An  account  of  some  of  the  investigations  in  which  the  foregoing 
methods   have  been  used   will   illustrate  their   value   in   revealing   the 


Fig.  4. — Apparatus  for  measurement  of  the  depression  of  freezing  point  of  solutions.  The 
solution  is  placed  in  the  large  test  tube  with  the  side  arm,  and  in  it  is  suspended  the  bulb 
of  a  Beckmann  thermometer  with  a  platinum  loop  to  serve  for  stirring.  The  upper  end  of 
the  mercury  column  of  the  thermometer  is  shown  magnified  at  the  upper  left  corner.  The 
amount  of  mercury  in  the  thermometer  tube  can  be  regulated  by  tapping  the  upper  end  with 
the  thermometer  in  various  positions.  The  test  lube  is  protected  by  an  outer  tube,  which  is 
then    placed    in    a    vessel    containing    a    freezing    mixture. 


mechanism  involved  in  the  transference  of  water  and  dissolved  sub- 
stances through  cell  membranes,  as  occurs  in  absorption  of  food  in  the 
intestine,  in  the  formation 'of  lymph  and  urine,  and  so  forth.  In  em- 
ploying physical  methods  in  the  elucidation  of  such  problems,  it  is 
always  most  necessary  to  proceed  with  great  care,  since  the  physical 


12       *  PHYSICOCHEMICAL   BASIS   OP   PHYSIOLOGICAL   PROCESSES 

chemist  works  with  pure-  solutions,  while  the  physiologist  has  to  use 
fluids  that  are  always  complicated  and  frequently  very  variable  in  com- 
position. We  must  simplify  the  problem  as  far  as  possible  by  having 
clearly  before  us  the  exact  nature  of  the  biological  problem  which  a  com- 
parison of  physicochemical  values,  such  as  osmotic  pressure,  may  ena- 
ble us  to  elucidate,  and  we  must  consider  the  other  physical  forces 
which  may  assist  or  modify  the  particular  one  we  are  investigating. 

In  the  physical  experiments  described  above,  the  semipermeable  mem- 
brane may  be  conceived  of  as  composed  of  pores  of  such  a  size  that 
they  permit  only  the  smallest  of  molecules — those  of  water — to  pass 
through  them.  Semipermeable  membranes  with  larger  pores  may,  how- 
ever, exist — that  is,  membranes  which  permit  water  molecules  and  mole- 
cules of  simple  chemical  substances  to  pass,  but  hold  back  those  com- 
posed of  large  complex  molecules.  Such  a  semipermeable  membrane 
would  allow  the  saline  constituents  but  not  the  proteins  of  blood  serum 
to  pass.  It  is,  hoAvever,  no  longer  semipermeable  towards  all  of  the  dis- 
solved substances,  and  the  process  of  diffusion  through  it  is  more  gener- 
ally designated  as  one  of  dialysis  than  of  osmosis. 

Since  the  passage  of  dissolved  molecules  through  membranes  de- 
pends upon  the  principle  of  diffusion,  its  rate  will  be  proportional  to 
the  osmotic  pressures  of  the  solutions  on  the  two  surfaces  of  the  mem- 
brane and  to  the  size  of  the  molecules,  small  molecules  diffusing  more 
quickly  than  large  ones.  Suppose  a  membrane  permeable  to  sodium 
chloride  and  water  is  placed  between  two  fluids  containing  sodium 
chloride  in  solution,  but  in  greater  concentration  in  one  of  them  than 
in  the  other:  the  sodium  chloride  will  diffuse  from  the  stronger  to  the 
weaker  solution,  and  water  will  diffuse  still  more  quickly  (because  its 
molecules  are  smaller)  in  the  opposite  direction,  until  the  number  of 
sodium-chloride  molecules  in  a  given  volume  of  solution  is  equal  on 
both  sides  of  the  membrane.  For  a  time,  therefore,  the  volume  of  the 
stronger  solution  Avill  increase.  The  differences  which  exist  in  the  dif- 
fusibility of  dissolved  molecules  are  analogous  to  those  which  have 
long  been  known  to  exist  in  the  diffusibility  of  gases,  but  the  relation 
between  rate  of  diffusibility  and  molecular  weight  is  not  so  simple  as 
the  ratio  between  these  two  quantities  in  gases.  These  relationships, 
however,  indicate  several  further  possibilities  in  the  explanation  of  the 
mechanism  of  exchange  of  substances  through  membranes,  and  must  not 
be  overlooked,  as  they  often  are,  in  the  interpretation  of  physiologic 
phenomena.  An  excellent  review  of  the  possible  conditions  is  given 
by  Starling  in  his  "Human  Physiology."4  For  example,  let  us  suppose 
the  substances  on  the  two  sides  of  a  semipermeable  membrane,  such 
as    the    peritoneal,    to    be    different    in    diffusibility,    as    cane    sugar, 


OSMOTIC   PRESSURE  13 

which  docs  noi  readily  diffuse,  and  sodium  chloride,  which  diffuses 
quickly;  the  osmotic  flow  will  lake  place  from  the  sodium-chlorid  solu- 
tion to  the  cane  sugar  even  when  the  sodium-chloride  solution  is  stronger 
than  the  sugar.  In  such  a  case,  water  molecules  will  pass  from  the  fluid 
having  the  higher  osmotic  pressure  (NaCl)  toward  a  fluid  in  which 
this  is  lower  (sugar). 

Furthermore,  the  simple  laws  of  osmosis  may  be  upset  by  an  attrac- 
tive influence  of  the  membrane  toward  certain  substances  [due  to  their 
becoming  dissolved  or  adsorbed  in  it  (see  page  65)]  but  not  toward 
others.  Many  membranes  of  this  nature  are  known  to  the  chemist 
(e.g.,  rubber  membranes  in  contact  with  gases,  pyridine  solutions,  etc.), 
and  it  is  probable  that  such  a  property  of  selective  solubility  may  play 
a  not  unimportant  role  in  the  transference  of  substances  across  animal 
membranes   (Kahlenberg5) . 

These  few  conditions  which  may  modify  the  direction  of  the  osmotic 
flow,  are  indicated  here  to  show  how  involved  such  problems  are,  and 
how  careful  we  must  be  not  to  assume  that,  because  a  substance  is  trans- 
ferred through  a  living  membrane  contrary  to  the  simpler  laws  of  os- 
mosia  and  diffusion,  it  must  involve  the  expenditure  of  forces  different 
from  those  operating  in  dead  membranes. 

Another  force  comes  into  operation  under  certain  conditions — namely, 
that  of  filtration.  This  is  a  purely  mechanical  process,  in  which  mole- 
cules are  forced  through  the  pores  of  a  filter  (i.  e.,  membrane)  by  dif- 
ferences in  pressure  on  its  two  sides. 

We  are  now  in  a  position  to  consider  in  how  far  the  above  physical 
forces  explain  certain  physiologic  problems. 

1.  Is  the  ab  sorption,  into  the  blooel  and  lymph  circulating  in  the  intes- 
tinal walls,  of  substances  in  solution  in  the  intestinal  contents  entirely 
dependent  upon  the  processes  of  filtration,  diffusion  and  osmosis?  The 
absorption  of  weak  solutions  of  highly  diffusible  substances  is  probably 
very  largely  a  matter  of  osmosis  and  diffusion,  and  water  passes  quickly 
into  the  blood  because  of  osmotic  attraction,  but  that  other  forces  ordi- 
narily come  into  play  is  very  clearly  established  by  the  following  ob- 
servations. If  a  piece  of  intestine  is  isolated  from  the  rest  by  placing 
two  ligatures  on  it,  and  the  isolated  loop  tilled  either  with  a  solution  con- 
taining the  same  saline  constituents  in  similar  proportions  as  in  blood 
serum,  or  better  still,  with  some  of  the  same  animal's  blood  serum,  it 
will  be  found  after  some  time  that  all  of  the  solution  becomes  absorbed 
into  the  blood ;  the  contents  of  the  loop  are  therefore  absorbed  into  the 
blood,  even  though  the  osmotic  pressures  of  the  dissolved  substances  are 
the  same  on  both  sides  of  the  membrane  (Weymouth  ReidG). 

The  intestinal  membrane  seems  to  possess  towards  readily  diffusible 


14  PHYSICOCHEMICAL    BASIS    OF   PHYSIOLOGICAL   PROCESSES 

substances  a  permeability  which  varies,  not  at  all  with  the  physical 
diffusibility  of  the  substance,  but  with  its  value  from  a  physiologic 
standpoint.  Thus,  sodium  sulphate  and  sodium  chloride  diffuse  through 
ordinary  membranes  with  about  equal  facility,  and  yet  if  a  solution  con- 
taining these  two  salts  is  placed  in  the  intestine,  the  chloride  will  be 
absorbed  into  the  blood  much  more  quickly  than  the  sulphate.  Sodium 
sulphate  in  watery  solution  diffuses  through  a  membrane  fifteen  times 
more  quickly  than  cane  sugar,  but  from  the  intestinal  lumen,  cane 
sugar  is  absorbed  ten  times  more  quickly  than  sodium  sulphate.  If. 
however,  the  vitality  of  the  epithelium  is  destroyed,  as  by  first  of  all 
bathing  it  with  a  solution  of  sodium  fluoride,  then  the  sulphate  and 
chloride  will  be  absorbed  at  an  equal  rate. 

Although  diffusion  and  osmosis  can  not  therefore  play  any  significant 
role  in  the  normal  process  of  absorption  from  the  intestine,  we  must 
not  entirely  discount  them ;  under  certain  circumstances,  these  physical 
forces  may  assert  their  influence  as,  for  example,  when  concentrated 
saline  solutions  are  present.  Such  solutions  will  attract  water  from  the 
blood,  and,  other  things  being  equal,  more  will  be  attracted  the  less 
permeable  the  epithelium  happens  to  be  towards  the  saline  employed. 
Sulphates  and  phosphates  will  attract  more  water  than  chlorides  or 
acetates.  This  property  of  the  saline  solutions  to  attract  water  coun- 
teracts the  natural  tendency  for  the  water  to  be  absorbed,  and  the 
large  volume  of  fluid  stimulates  peristalsis. 

2.  Do  the  physical  processes  of  -filtration,  diffusion  and  osmosis  suf- 
fice to  account  for  the  production  of  urine  by  the  kidneys?  Under  normal 
conditions  the  molecular  concentration  of  the  urine,  as  determined  by 
the  depression  of  freezing  point,  is  considerably  greater  than  that  of 
the  blood.  This  indicates  that  excretion  must  have  occurred  contrary 
to  the  laws  of  osmosis;  in  other  words,  that  the  renal  cells  must  have 
compelled  dissolved  molecules  to  be  transferred  from  the  blood  to  the 
urine,  although  the  difference  in  osmotic  pressure  would  cause  them  to 
pass  in  the  opposite  direction.  This  force,  sometimes  called  for  want 
of  a  better  name  "vital  activity."  must  depend  on  the  operation  of 
processes  that  are  quite  distinct  from  those  of  diffusion,  etc.;  but  that 
they  are  necessarily  of  a  nonphysical  nature  (e.  g.,  vital)  is  less  probable 
than  that  they  depend  on  some  physical  process  the  nature  of  which  our 
present  knowledge  does  not  permit  us  to  understand. 

By  comparing  the  osmotic  pressures  of  urine  and  blood,  attempts 
have  been  made  to  measure  the  work  done  by  the  kidney  in  the  produc- 
tion of  urine.  Thus,  it  has  been  found  that  A  for  normal  urine  (human) 
is  about  1.8.  and  for  blood  about  0.6,  from  which  it  may  be  calculated 
that  in  the  production  of  1  kilogram  of  urine  150  kilogrammeters  of 


OSMOTIC    PRESSURE  1  .*> 

work  are  expended.*  But  that  such  comparisons  of  t  ho  osmotic  pres- 
sure of  blood  and  urine  are  fallacious  as  an  indication  of  the  work  of 
the  kidney  is  evidenced,  not  alone  by  the  results  of  the  above  calcula- 
tions, but  also  by  the  fact  that  under  certain  circumstances  (as  after 
copious  diuresis)  the  osmotic  pressure  of  the  urine  may  be  considerably 
lower  than  that  of  the  blood.  That  opposite  relationships  should  exist 
indicates  that  differences  in  osmotic  pressure  between  blood  and  urine 
can  signify  little  if  anything  regarding  the  work  done  by  the  kidney. 

For  some  time  after  the  application  of  osmotic  pressure  measurements 
to  the  study  of  biological  problems,  it  was  thought  that  determination 
of  A  in  urine  might  be  of  clinical  value  as  a  criterion  of  renal  efficiency, 
especially  in  one  kidney  as  compared  with  the  other.  For  this  purpose 
A  was  determined  in  samples  of  urine  removed  from  each  ureter  by 
catheterization.  The  tests  of  renal  efficiency  based  on  the  rate  of  excre- 
tion of  potassium  iodide,  phenolphthalein,  etc.,  have  however  been  found 
of  much  greater  value. 

3.  7s  the  formation  of  lymph  purely  a  physical  process?  The  osmotic 
pressure  of  normal  lymph  is  nearly  always  somewhat  below  that  of 
blood  serum,  although  occasionally  it  has  been  found  to  be  a  trifle 
higher.  Physical  processes,  such  as  filtration,  might  therefore  suffice 
to  account  for  its  formation  under  most  conditions.  But  when  we  con- 
sider the  excessive  production  of  lymph  that  occurs  as  a  result  of  cel- 
lular activity  or  following  the  injection  of  certain  substances,  called 
"lymphagogues,"  it  is  not  so  easy  to  explain  the  production  in  such 
termSj  although  some  interesting  attempts  have  been  made  to  do  so  by 
those  that  are  wedded  to  the  mechanistic  view.  For  example,  the  very 
marked  increase  in  lymph  flow  which  occurs  as  a  result  of  muscular 
exercise  or  glandular  activity  has  been  attributed  to  the  fact  that  dur- 
ing such  processes  large  molecules  become  broken  down  into  small  ones 
in  the  cell  protoplasm,  so  that  the  osmotic  pressure  is  raised  and  water 
is  attracted  into  the  the  cell  until  the  latter  becomes  distended  and  a 
process  of  filtration  into  the  neighboring  lymph  spaces  occurs  (see 
page  119). 

There  are  several  other  physiologic  processes  of  secretion  and  excre- 
tion which  might  be  considered  in  the  present  relationship,  but  the  above 
instances  will  suffice  to  illustrate  the  general  principle  upon  which  all  of 
them  have  to  be  considered. 


*()smotic  pressure  corresponding  to  A  =  -0.6°  C.  equals  5,662  mm.  Hg  (75  m.  of  HoO),  and 
that  corresponding  to  A  =  "1-8°  C.  equals  16.9S6  mm.  Hg  (225  m.  H20).  The  difference  is  there- 
fore equal  to  a  column  of  water  150  m.  high.  According  to  these  calculations  it  would  appear  that 
the  kidney  in  producing  the  average  daily  output  of  1500  c.c.  urine  performs  225  kilogrammeters  of 
work  in  comparison  with  the  14,000  kilogrammeters  which  the  heart  is  computed  to  perform  in  the 
same   time    (page   212). 


CHAPTER  III 
ELECTRIC  CONDUCTIVITY,  DISSOCIATION,  AND  IONIZATION 

The  osmotic  pressure  is  not  infrequently  found  to  be  considerably 
greater  than  that  expected  from  the  strength  of  the  solution.  Although 
A  of  a  gram-molecular  watery  solution  of  cane  sugar  (342  gm.  to  the  liter) 
is  1.86  (see  page  10),  that  of  sodium  chloride  (58.5  gm.  to  the  liter)  is. 
considerably  greater.  If  the  hypothesis  regarding  the  relationship  of 
molecular  concentration  to  osmotic  pressure  is  to  hold  good,  it  becomes 
necessary  to  explain  this  apparent  inconsistency;  one  must  account  for 
a  greater  number  of  dissolved  units  than  is  represented  by  the  actual 
number  of  dissolved  molecules  (i.e.,  weight  of  dissolved  substances). 

It  was  observed  that  the  power  to  conduct  the  electric  current — electric 
conductivity — in  the  case  of  solutions  (e.  g.,  of  sugar)  which  have  an 
osmotic  pressure  that  corresponds  to  the  weight  of  dissolved  substances 
is  practically  nil,  whereas  the  conductivity  of  those  solutions  which  i^ive 
higher  osmotic  pressure  is  quite  pronounced.  Arrhenius  made  the  hy- 
pothesis that  the  conductivity  depends  on  the  splitting  of  molecules  into 
two  or  more  portions  or  ions,  each  of  which  carries  either  a  positive  or  a 
negative  electric  charge,  and  that  it  is  only  when  such  dissociation  occurs 
that  the  electric  current  can  be  conducted  through  the  solution,  the  ions 
serving  as  it  were  as  floats  carrying  the  electric  current.  When  sodium 
chloride  is  dissolved  in  water,  it  splits  into  Na  carrying  a  positive  charge 
and  CI  carrying  a  negative  charge,  or  Na  +  CI  -,  as  it  is  written ;  on  the 
other  hand,  when  sugar  is  dissolved,  the  molecules  remain  unbroken  and 
no  electric  charges  are  set  free. 

Substances  which  thus  dissociate  are  called  electrolytes,  and  those  which 
do  not,  non-electrolytes.  When  the  electric  current  is  passed  through  a 
solution  of  electrolytes,  the  ions  which  carry  a  positive  charge  move  to 
the  electrode  or  pole  by  which  the  current  leaves  the  solution — that  is,  in 
the  same  directions  as  the  current;  and  since  this  electrode  is  called  the 
cathode,  these  are  called  cations.  Hydrogen  and  the  metals  belong  to 
this  group.  The  ions  carrying  a  negative  charge  go  in  the  opposite  direc- 
tion, against  the  current — that  is,  towards  the  electrode  by  which  the  cur- 
rent enters,  or  the  anode;  they  are  therefore  called  anions.  They  include 
oxygen,  the  halogens  and  the  acid  groups,  such  as  S04,  C03,  etc. 

It  must  be  understood  that  this  dissociation  into  ions  is  already  present 
in  the  solution  before  any  electric  current  passes  through  it,  the  ions 

16 


ELECTRIC  CONDUCTIVITY,  DissociA'i'iox,  ionization  17 

being  however  uniformly  distributed  throughout — that  is,  arranged  so 
thai  the  negative  charges  of  the  anions  precisely  neutralize  the  positive 
charges  of  the  cations.  The  electric  current  causes  the  electrodes  to  be- 
come charged,  the  one  positively,  the  other  negatively,  so  that  an  attrac- 
tive force  is  exerted  on  the  ions  of  opposite  sign.  This  causes  the  nega- 
tively charged  ions  to  migrate  towards  the  positive  electrode,  and  the 
positively  charged,  towards  the  negative  electrode.  It  is  this  migration 
of  the  ions  that  endows  the  solution  with  conducting  qualities. 

In  water,  or  in  a  solution  of  a  nonelectrolyte,  molecules  of  H20  or  non- 
electrolyte  exist   thus: 

B20  IT/)  H20 

H20  11,0  11,0 

11,0  11,0  11,0 

In  a  solution  of  an  electrolyte,  the  molecules  split  into  ions  thus: 

Xa«     01-     Na*     Ch     Na<     Cl- 

Na*    CI-     Na*     CI-     Na*     Cl- 
Na*     CI-     Na*     CI-     Na-     01- 

When  an  electric  current  passes  through  a  solution  of  an  electrolyte, 
the  ions  tend  to  arrange  themselves  thus: 


Cathode- 

Anode 

Na*     Xa  • 

Na* 

ci- 

01- 

ci- 

Na*    Na* 

Na* 

01- 

ci- 

ci- 

Na*    Na* 

Na* 

ci- 

ci- 

ci- 

It  follows  from  the  above  considerations  that  the  conductivity  of  a  sub- 
stance in  solution  will  depend  on  the  degree  to  u'lii<ilt  it  undergoes  dissocia- 
tion. Furthermore,  if  we  assume  that  in  so  far  as  osmotic  pressure 
phenomena  are  concerned,  each  ion  behaves  in  the  same  way  as  a  mole- 
cule, then  it  follows  that  the  electrical  conductivity  must  be  proportional 
to  the  extent  to  which  the  osmotic  pressure  is  greater  than  we  should  ex- 
pect it  to  be  from  the  amount  of  substance  actually  dissolved. 

In  the  Determination  of  the  Conductivity  it  is  obviously  necessary  to 
use  standard  conditions  of  depth  and  width  of  the  fluid  through  which  the 
current  is  passed,  and  to  have  some  standard  of  comparison.  The  value 
is  then  known  as  the  specific  conductivity,  the  standard  for  comparison 
being  the  conductivity  of  a  hypothetical  liquid  which,  if  enclosed  in  a 
centimeter  cube,  would  offer  a  resistance  of  1  ohm  between  two  opposite 
sides  of  the  cube  acting  as  electrodes.      The  actual  determination  is  usu- 


18 


physicochUmical  basis  of  physiological  processes 


ally  made  in  a  cylindrical  vessel  of  hard  glass  (from  soft  glass  enough 
alkali  might  be  dissolved  to  affect  the  results),  the  electrodes  being  circu- 
lar plates  of  platinum  firmly  cemented  at  a  known  distance  from  each 
other  (Fig.  5).*  This  conductivity  cell,  as  it  is  called,  is  connected 
with  a  suitable  electric  apparatus  for  measuring  the  resistance  offered 


Fig.  5. — Diagram  of  conductivity  cells.  The  platinum  discs  are  represented  bv  the  thick 
black-  lines.  They  are  held  in  position  by  thick-walled  glass  tubes,  through  which  they  are 
connected    with    the    terminals    by    platinum    wires.       (From     Spencer.) 

by  the  solution  to  the  passage  of  an  electric  current  (Wheatstone  Bridge) 
(see  Fig.  6).  The  resistance  is  of  course  inversely  proportional  to  the 
conductivity. 

As  a  saline  solution  is  progressively  diluted,  its  specific  conductivity 
naturally  decreases  (since  there  are  now  fewer  molecules  between  the 


Fig.     6. — Wheatstone     Bridge     for     the     measurement     of     electric     resistance:     a-b,     bridge     wire;     c, 

the    movable    contact. 


two  opposite  faces  of  the  centimeter  cube,  and  the  space  between  ions  or 
molecules  is  increased).  This  result  will  not,  however,  tell  us  whether 
the  salt  itself  is  undergoing  any  alteration  in  conducting  power  as  a  con- 
sequence, for  example,  of  greater  dissociation.    To  ascertain  this  we  must 


*This  distance  is  determined  not  by  direct  measurement  but  by  calculation  from   results  obtained 
by  testing  the  actual  resistance  of  a  solution  whose  specific   resistance  is  accurately  known. 


ELECTRIC  CONDUCTIVITY,   DISSOCIATION,   IONIZATION  19 

obtain  figures  relating  to  the  same  quantity  of  salt  at  each  dilution.  If 
we  multiply  the  specific  conductivity  by  the  volume  of  solution  in  c.c. 
which  contains  1  gram-equivalent  (see  page  22),  a  value  will  he  secured 
•which  represents  the  conducting  power  of  a  gram-equivalent.  This  is 
known  as  the  equivalent  or  molecular  conductivity*  and  is  represented  by 
the  sign  A.  When  it  is  determined  for  progressively  diluted  solutions, 
A  gradually  increases,  indicating  that  the  efficiency  of  the  electrolyte  itself 
as  a  conductor  increases  with  dilution,  because  it  dissociates  more.  The 
extent  of  this  increase  is  found  to  become  less  and  less  as  dilution 
proceeds.  By  plotting  the  values  of  the  molecular  conductivity  of  suc- 
cessive dilutions  as  a  curve,  the  value  at  infinite  dilution  can  be  ascertained 
by  extrapolation.    This  value  is  represented  by  Ace. 

Now,  let  us  see  how  these  facts  bear  out  the  theory  of  electrolytic  dissocia- 
tion. According  to  this  hypothesis  the  conductivity  depends  on  the  num- 
ber of  ions  (see  page  17),  and  since  it  is  at  a  maximum  at  infinite  dilu- 
tion, the  value  Aoc  must  represent  the  total  number  of  ions  that  can  be  pro- 
duced by  the  dissociation  of  1  gram-equivalent,  and  A  that  at  some  other 
dilution.  If,  therefore,  we  divide  A  by  Ace  we  obtain  a  value  (called  a) 
which  must  represent  the  degree  to  which  the  electrolyte  is  ionized  at  the 
various  dilutions  at  which  A  is  measured.  From  what  has  been  said  re- 
garding the  osmotic  pressure  of  similar  solutions,  it  is  evident  that  the 
value  a  could  also  be  calculated  by  finding  the  extent  to  which  the  de- 
pression of  freezing  point  A  is  greater  than  would  be  expected  from  the 
number  of  dissolved  molecules.  As  a  matter  of  fact,  it  has  been  found 
that  practically  identical  values  are  obtained  for  many  substances,  thus 
furnishing  almost  incontrovertible  proof  in  support  of  the  dissociation 
hypothesis.  In  the  cases  of  weak  acids  and  bases,  it  is  possible  to  secure 
a  value,  called  the  dissociation  constant  (K),  which  represents  the  rela- 
tive values  of  a  at  all  dilutions.  Since  the  activity  of  acids  and  bases 
is  dependent  upon  the  number  of  IT-  and  OH-ions,  respectively,  set  free 
by  dissociation,  it  follows  that  it  must  be  proportional  to  K.  It  will  be 
necessary  to  postpone  a  consideration  of  the  application  of  this  constant 
until  we  have  studied  mass  action  (page  23). 

Biological  Applications. — The  practical  value  of  such  knowledge  rests, 
not  so  much  on  any  direct  simple  application  that  can  be  made  of  it  in 
explaining  physiologic  processes,  as  on  the  essentially  important  bearing 
which  it  has  in  enabling  us  to  understand  the  nature  and  operation  of 
other  physicochemical  factors  concerned  in  physiologic  processes.  With- 
out a  clear  comprehension  of  the  elemental  laws  of  dissociation,  it  is 
impossible  to  consider  such  problems  as  those  which  concern  the  activities 


•In  other  words,  the  molecular  conductivity  is  the  specific  conductivity  divided  by   the  number  of 
gram-equivalents  contained  in   1  c.c. 


20  PHYSICOCHEMICAL    BASIS   OF    PHYSIOLOGICAL   PROCESSES 

of  enzymes  (mass  action,  etc.),  the  occurrence  of  electric  currents  during 
the  physiologic  activity  of  muscles,  glands,  and  nerves,  and  the  all- 
important  question  of  the  reaction  or  II  ion  concentration  of  the  body 
fluids. 

Before  proceeding  to  show  how  these  facts  concerning  the  nature  of 
solutions  are  applicable  to  the  study  of  physiologic  processes,  it  may  be 
well  to  indicate  one  or  two  instances  in  which  measurements  of  electrical 
conductivity  and  of  dissociation  have  direct  physiologic  value.  The  circu- 
lation time  of  the  bloodflow  through  an  organ  can  be  determined  by  first 
finding  the  electrical  resistance  of  a  short  piece  of  the  vein  of  the  organ, 
and  then  observing  the  change  in  resistance  which  is  produced  when  the 
conductivity  of  the  blood  in  the  vein  is  altered  by  the  arrival  in  it  of 
saline  injected  into  the  artery.  The  interval  elapsing  between  the  injec- 
tion into  the  artery  and  the  changes  in  resistance  in  the  vein  obviously 
equals  the  circulation  lime  ((}.  N.  Stewart). 

The  same  investigator  has  used  measurements  by  electrical  conductiv- 
ity to  study  the  passage  of  electrolytes  out  of  the  red  blood  corpuscles  into 
the  serum.  Under  normal  conditions  the  blood  serum  has  a  certain  elec- 
trical conductivity  equal  to  that  of  a  0.?)  per  cent  sodium-chloride  solution. 
The  conductivity  of  the  defibrinated  blood  is  only  about  one-half  that  of 
serum,  because  it  contains  corpuscles  which  are  nonconductors  and  there- 
fore obstruct  the  free  passage  of  the  ions,  just  as  a  suspension  of  quartz 
powder  in  a  sodium-chloride  solution  lowers  the  conductivity  of  the  lat- 
ter. Tf  anything  occurs  therefore  to  occasion  a  passage  of  the  saline  con- 
tents of  the  corpuscles  through  their  Avails  into  the  serum,  an  increase  in 
the  electric  conductivity  will  be  produced.  The  value  of  this  method  in 
the  investigation  of  changes  in  permeability  of  the  red  corpuscles  is  de- 
pendent on  the  fact  that  such  migration  of  electrolytes  out  of  the  cor- 
puscles may  occur  before  any  of  the  less  diffusible  hemoglobin  itself  has 
escaped.     The  rise  in  conductivity  precedes  the  hemolysis  (see  page  7). 

Although  determinations  of  the  specific  conductivity  of  blood  and  urine 
under  various  pathologic  conditions  have  also  been  made,  the  results 
have  not  been  found  to  possess  any  diagnostic  value  or  clinical  signifi- 
cance. Measurements  of  the  electric  conductivity  of  blood  have,  how- 
ever, been  used  by  Wilson7  and  by  Priestley  and  Haldane8  to  detect  the 
degree  of  dilution  when  large  quantities  of  water  are  ingested. 

Another  application  of  conductivity  measurements  in  biochemistry  has 
been  made  in  studying  the  digestive  action  of  proteolytic  enzymes  (Bay- 
liss).  The  general  action  of  the  enzymes  is  to  break  the  large  undisso- 
ciated  molecules  of  the  higher  proteins  (albumin,  casein,  etc.),  into 
smaller  molecules  (amino  acids,  etc.),  which  are  partly  ionized.    As  diges- 


ELECTRIC  CONDUCTIVITY,   dissociation,    IONIZATION  21 

tion  proceeds,  therefore,  the  conductivity  of  the  digestion  mixture  pro- 
gressively increases,  and  is  a  measure  of  the  rate  of  digestion. 

Applications  of  the  dissociation  hypothesis  in  physiology  concern  the 
explanation  of  such  phenomena  as  the  production  of  electric  currents 
during  muscular,  glandular,  and  oervous  activity.    The  exacl  details  of 

the  application  are  not  as  yet  sufficiently  understood  to  \varr;oi1  our  at- 
tempting to  do  more  than  indicate  the  general  lines  along  which  the 
problems  are  being  investigated.    Let  us,  for  example,  consider  how  the 

CUrrenl  of  action  of  muscle  may  he  explained  in  terms  of  the  dissociation 
hypothesis.  To  do  so  we  must  delve  a  little  further  into  physicochem 
ical  research,  when  we  shall  find  thai  there  are  two  further  facts  con- 
cerning Ionized  molecules  that  must  he  of  importance  in  connection  with 
our  problem.  The  first  is  that  the  contribution  which  each  ion  makes  to 
the  equivalent  (or  molecular)  conductivity  of  a  solution  is  independent 
of  the  other  ion  with  which  it  is  associated;  and  the  second,  that  ions 
differ  considerably  in  their  conducting  power.  Since  the  univalent  ions, 
K.,  Na.,  CI/,  NO/,  carry  charges  of  the  same  magnitude,*  and  ye1  all  do 
not  conduct  to  the  same  degree,  they  must  move  at  different  velocities 
through  the  solution.  We  are  driven,  therefore,  to  the  conclusion  that, 
exposed  to  the  same  electric  force,  different  ions  have  different  mobili- 
ties; thai  is  to  say,  when  an  electric  current  passes  through  a,  solution  of 
an  electrolyte,  the  positively  charged  ions  move  towards  the  cathode  al  a 
different  rate  from  that  at  which  the  negatively  charged  ions  move 
towards  the  anode.  Confirmation  of  this  conclusion  is  obtained  by  exam- 
ination of  the  concentration  changes  around  the  two  electrodes  of  an 
electrolytic  cell.  The  actual  velocity  of  each  ion  can  be  determined  by 
experimental  means. 

•Thus  Faraday  showed  that  the  amounts  of  the  various  ions  liberated  l>y  electrolysis  are  in  the 
same  ratio  as  their  chemical  equivalents. 


CHAPTER  IV 

THE  PRINCIPLES  INVOLVED  IN  THE  DETERMINATION  OF  THE 
HYDROGEN-ION  CONCENTRATION 

TITRABLE  ACIDITY  AND  ALKALINITY 

All  acids  have  one  property  in  common — namely,  that  they  contain 
hydrogen — and  when  the  acid  becomes  neutralized,  it  is  this  element 
which  becomes  replaced  by  some  other  cation.  Evidently,  then,  the 
strength  of  an  acid  is  proportional  to  the  number  of  displaceable  hydro- 
gen atoms  which  it  contains.  It  may  contain  other  hydrogen  atoms 
which  are  so  bound  up  in  the  molecule  that  they  do  not  become  displaced 
when  an  alkali  is  mixed  with  the  acid.  For  example,  in  organic  acids 
like  acetic,  CH3COOH,  it  is  only  the  II  atom  attached  to  the  COOH 
group,  but  not  those  attached  to  the  CH3  group,  that  is  replaceable.  It 
must  therefore  be  possible  to  prepare  for  every  acid  a  solution  having 
exactly  the  same  neutralizing  power  as  that  of  any  other  acid;  that  is, 
the  same  volume  of  solution  must  be  required  in  each  case  to  neutralize 
a  given  quantity  of  alkali,  the  point  of  neutralization  being  judged  by 
the  change  in  color  of  indicators.  As  a  standard  a  gram-molecular  solu- 
tion of  an  acid  with  one  displaceable  H  ion,  such  as  hydrochloric,  is 
chosen.  This  we  call  a  "normal  acid"  (N).  To  prepare  a  normal  solu- 
tion of  acids  having  two  displaceable  II  atoms,  such  as  H2S04,  Ave  can  not 
however  use  a  gram-molecular  quantity,  but  must  take  one-half  of  it; 
and  similarly  in  the  case  of  those  with  three  H  atoms,  such  as  H3P04, 
a  one-third  gram-molecular  solution  will  be  a  normal  acid  solution.  For 
practical  purposes,  use  is  very  generally  made  of  solutions  that  are  some 
fraction  of  the  normal,  e.  g.,  tenth  or  decinormal  (written  N/10),  or  hun- 
dredth or  centinormal  (N/100). 

In  a  similar  way,  alkaline  solutions  can  be  prepared,  a  normal  alkali 
being  one  which  exactly  corresponds  in  strength  with  a  normal  acid 
(i.e.,  can  exactly  neutralize  it).  Now,  the  characteristic  of  alkalies  is 
that  they  produce  in  solution  ' '  OH ' '  or  hydroxy!  ions ;  so  that  the  process 
of  neutralization  must  consist  in  the  union  of  the  H  ions  of  the  acid  with 
the  OH  ions  of  the  alkali  to  form  water:  KOH  +  HC1  =  KC1  +H20.  We 
can,  therefore,  prepare  normal  solutions  of  alkalies  by  dissolving  in  1 
liter  of  water  such  quantities  of  alkali  (in  grams)  as  will  yield  the  OH 
required  to  react  with  the  available  hydrogen  in  normal  acid  solutions. 

22 


HYDROGEN-ION    CONCENTRATION 


23 


Actual  Degree  of  Acidity  or  Alkalinity.  According  to  the  foregoing 
method  of  titration  a  normal  solution  of  a  powerful  mineral  acid,  such 
as  hydrochloric  is  no  stronger  than  a  normal  solution  of  a  weak  acid, 
such  as  acetic  or  lactic.  It  requires  no  fewer  c.c.  of  N  alkali  to  neutralize 
it.  But  the  normal  solution  of  the  powerful  acid  tastes  more  acid,  is 
more  toxic,  dissolves  metals  more  readily,  and  in  all  its  other  chemi<;il 
and  physiologic  properties  acts  much  more  quickly  than  the  weak  acid, 
so  that  the  titrable  acidity  or  alkalinity  can  not  express  the  real  strength 
of  the  acid  or  alkali,  or  the  actual  degree  of  acidity  or  alkalinity.  It  is 
in  this  connection  that  the  dissociation  hypothesis  aids  us,  for  it  suggests 
that  the  degree  to  which  the  acid  becomes  dissociated  into  H'  and  the 
remainder  of  the  molecule  will  determine  its  real  strength  (see  page  16). 
The  question  is,  how'  are  we  to  measure  the  latter?  One  action  of  H  ions 
which  we  may  measure  is  that  known  as  catalytic — that  is,  the  power  to 
accelerate  reactions,  such  as  the  splitting  of  cane  sugar  (C^IL^On)  into 
glucose  and  levulose,  which  otherwise  would  proceed  very  slowly  (see 
page  75).  If  then  the  real  strength  of  an  acid  depends  on  the  degree 
of  dissociation  which  it  undergoes,  figures  representing  the  catalytic 
power  should  correspond  with  those  representing  the  relative  conductivi- 
ties of  the  acids  in  equivalent  concentration  (see  page  19).  That  this  is 
actually  the  case  is  shown  in  the  following  table,  in  which  the  above  values 
of  various  acids  are  given  compared  with  HC1,  which  is  taken  as  100. 


CATALYTIC  POWER 


RELATIVE  CONDUCTIVITY 


HC1 

100 

Dichloracctic 

27 

Monoehloracetic 

4.8 

Formic 

1.5 

Acetic 

0.40 

100 
25 
4.9 
1.7. 
0.42 


It  will  be  evident  that,  if  we  could  measure  the  concentration  of  free 
H  ions  in  a  solution — that  is,  of  H  ions  that  are  not  matched  by  OH  ions — - 
avc  should  have  a  faithful  index  of  its  real  acidity.  This  measurement 
has  been  rendered  possible  by  the  application  of  two  other  physico- 
chemical  principles — namely,  those  of  mass  action  and  electromotive 
force.  Since  the  object  of  this  volume  is  to  present  the  scientific  basis 
for  the  various  methods  that  are  used  in  modern  medicine,  it  wall  be  nec- 
essary for  us  to  review  the  main  principles  of  these  two  actions.  We  shall 
see  that  they  apply,  not  only  in  the  measurement  of  H-ion  concentration, 
but  in  many  other  physiologic  processes. 

Mass  Action 

When  materials  take  part  in  a  reaction,  some  molecules  are  decom- 
posing while  others  are  being  formed.     After  some  time,  however,   a 


24  PHYSICOCHFyMICAL  basis  of  physiological  processes 

condition  is  reached  in  which  the  changes  in  one  direction  are  exactly 
offset  by  those  in  the  other.  An  equilibrium  is  said  to  have  become  estab- 
lished between  the  reacting  substances.  Bearing  in  mind  that  the  ions 
and  molecules  entering  into  these  reactions  are  constantly  moving  about 
and  coming  in  contact  with  one  another,  it  is  easy  to  see  that  if  we  were 
to  add  an  additional  quantity  of  one  kind  of  molecule  or  ion,  there  would 
be  a  change  all  along  the  line  until  a  new  equilibrium  was  established. 
If,  on  the  other  hand,  we  were  to  remove  one  kind  of  molecule  or  ion 
as  fast  as  it  is  formed,  the  equilibrium  could  never  be  established,  and 
the  reaction  would  proceed  until  all  of  this  material  had  disappeared. 
The  natural  rate  at  which  any  chemical  reaction  proceeds  is  dependent 
upon  a  number  of  conditions,  such  as  chemical  affinity,  temperature, 
catalysis,  and  concentration.  Of  these  conditions  that  of  concentration 
is  most  readily  measured.  If  we  maintain  all  of  the  conditions  other 
than  that  of  concentration  unchanged,  and  designate  this  combined  in- 
fluence as  K  (constant),  we  shall  find  that  the  speed  of  the  reaction  is 
proportional  to  the  molecular  concentration  of  the  reacting  substances 
(i.  e.,  the  number  of  gram-molecular  weights  per  liter).  In  other  words, 
the  speed  with  which  two  substances,  a  and  b,  unite  to  form  other  sub- 
stances, c  and  d,  will  be  expressed  by  the  equation, 

k    (a)  x  (1»)   =±  k'    (c)  x  (d)  ;* 

which   means  that,   when   the   reaction  is   complete,   the   composition   of 

the  mixture  will  be  dependent  upon  the  ratio  between  k  and  k'.     Since 

however  these  are  both  constants,  their  quotient  is  also  constant   (K),  and 

(a)  x (b) 
we  have  the  equation,  -7— r — t-tt-  =  K,  indicating  that  no  matter  how 

(c)  x (d) 

the  concentrations  a,  b,  c,  and  d  are  varied,  reaction  will  take  place  in 
one  direction  or  the  other  until  the  concentrations  have  become  adjusted 
so  that  K  remains  unchanged. 

As  an  example  of  the  application  of  these  laws,  let  us  take  the  reaction 
which  occurs  between  alcohols  and  organic  acids  to  form  the  substances 
called  esters — a  reaction  which  is  analogous  to  that  between  mineral 
alkalies  and  acids  to  form  neutral  salts,  and  which  is  of  special  interest 
to  us  because  it  is  the  reaction  involved  in  the  splitting  of  animal  fats. 
The  equation  for  the  reaction  is: 

C,H,OIH  CILCOOH  ^=  OJLOOCCIL-t  1U>. 
(ethyl  (acetic  (ethyl  acetate, 

alcohol)         acid)  an  ester) 

Or  expressed  according  to  the  law  of  mass  action: 

[C2H5OH]  x  [CILCOOH] 


[C2H5OOCCH3]  x  [HX>] 


K. 


"The    brackets   indicate    that   gram    molecular   quantities    are    used. 


HYDROGEN-ION    CONCENTRATION  25 

Now  it  is  clear  that  it'  we  increase,  say,  H20  in  the  above  equation,  then 
in  order  thai  K  may  remain  unchanged  C2H5OOCCH8  musl  diminish  or 
the  substances  which  form  the  numerator  of  the  equation  must  increase, 
or  both  these  changes  must  occur.    As  a  matter  of  fact,  in  such  a  case  as 

the  above,  both  of  these  adjustments  lake  place,  for,  as  the  ester  breaks 
down,  it  must  thereby  increase  the  concentration  of  acid  and  alcohol. 
Since  in  aqueous  solutions  tin'  reaction  occurs  in  the  presence  of  an  excess 
of  water,  it  is  evident  that  the  tendency  for  an  ester  in  the  presence  of 
water  is  to  break  down  into  alcohol  and  acid,  and  this  ninsl  occur  in  all 
reactions  in  the  body  fluids  in  which  water  enters  into  the  equation. 

Physiologic  Applications. — The  application  of  the  law  of  mass  action 
in  the  explanation  of  biochemical  processes  is  very  extensive.  Most  of 
the  reactions  which  enzymes  or  ferments  are  capable  of  influencing  are 
of  the  same  general  nature  as  that  represented  above,  and  the  products 
of  their  activities  are  usually  the  substances  on  the  side  of  the  equation 
in  which  no  water  molecules  appear — i.  e.,  they  are  hydrolytic  reactions. 
Enzymes  merely  accelerate  the  reaction  (page  72),  so  that  if  we  start 
with  a  mixture  of  the  substances  on  cither  side  of  the  equation,  all  they 
do  is  to  accelerate  the  production  of  a  sufficient  concentration  of  those 
on  the  other  side,  until  the  equilibrium  point  is  reached.  For  example, 
an  enzyme  present  in  pancreatic  juice,  called  lipase,  accelerates  the 
breakdown  of  such  esters  as  neutral  fat,  which  consists  of  the  triatomic 
alcohol,  glycerol,  combined  with  the  fatty  acids  palmitic  (C15H31COOH)., 
stearic  (C„H35COOH)  and  oleic  (C7II,3COOH): 

C3H5   (O  OC  C17H35)3f  3H,0  <=±  3C)7H3rOOOH  +  C3Hr,   (OH)3. 

(the    neutral    tat,  (the  fatty  acid,     (glycerol) 

tristearin)  stearic) 

Under  ordinary  conditions  the  reaction  proceeds  until  nearly  all  the 
neutral  fat  has  become  decomposed  because  of  the  preponderance  of 
water,  but  if  we  start  with  a  mixture  of  fatty  acid  and  glycerol  with 
just  enough  water  to  permit  the  enzyme  to  act,  the  reaction  will  pro- 
ceed in  the  opposite  direction — i.  e.,  so  that  some  neutral  fat  will  be 
synthesized.     This  is  called  the  reversible  action  of  enzymes. 

Because  of  the  universal  presence  of  water,  it  is  plain  that  such  re- 
versible reactions  could  not  alone  be  held  responsible  for  the  synthe- 
sis of  neutral  fat  or  of  similar  substances  in  the  animal  body.  The  only 
May  by  which  synthesis  could  occur  under  these  conditions  "would  be 
if  the  substance  produced  along  with  the  water  were  removed  from  the 
site  of  the  reaction  as  soon  as  it  wTas  formed.  This  might  occur  by  the 
precipitation  of  the  substance  or  by  its  becoming  surrounded  by  an  en- 
velope of  some  inert  material.     In  the  synthesis  of  neutral  fat  which 


26  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

occurs  in  the  epithelium  of  the  intestine  out  of  the  fatty  acid  and  glycerol 
absorbed  from  the  intestinal  contents,  it  is  possible  that  the  last  men- 
tioned process  occurs.  In  other  cases  the  substance  may  be  carried 
away  by  the  blood  or  lymph  or  urine  as  fast  as  it  is  formed. 

The  Law  of  Mass  Action  as  Applied  to  the  Measurement  of  H-ion 
Concentration. — Let  us  now  return  to  the  reaction  or  H-ion  concentration 
of  substances  in  solution.  As  the  standard  of  neutrality,  pure  water  is 
chosen.  Let  us  consider,  then,  how  the  laws  of  mass  action  can  be 
applied  in  order  to  enable  us  to  determine  the  H-ion  concentration  of 
pure  water.  It  has  been  stated  above  that  chemically  pure  water  is  in- 
capable of  conducting  the  electric  current.  This  however  is  not  strictly 
the  case,  for  it  conducts  to  a  very  slight  degree.  According  to  the  dis- 
sociation hypothesis,  it  must  therefore  be  represented  as  containing 
molecules  of  H20  and  ions  of  II-  and  OH',  and  according  to  that  of  mass 
action  there  must  be  a  balanced  reaction  between  the  molecules  and  ions 
represented  thus: 

lH-]x[OH'] 

H,0  <=±  H'  +  OH',  or  - — f^ft^ L  =  K. 

[H2UJ 

Since  the  concentration  of  H-  and  OH'  is  extremely  small,  there  must 
always  be  such  an  overwhelming  preponderance  of  H20  molecules  that 
no  changes  in  the  concentration  of  H-  and  OH'  will  be  capable  of  appre- 
ciably affecting  the  concentration  of  H20 ;  in  other  words,  one  may  omit 
the  denominator  of  the  equation  and  write  it  [H-]  x  [OH']  =  K.  If 
then  we  know  the  value  of  K,  it  will  only  be  necessary  to  measure  the 
concentration  of  either  H-  or  OH'  in  order  to  express  in  numerical  terms 
the  reaction  of  the  solution.  It  has  been  found  that  the  value  of  K  is 
about  1  x  10"14,*  and  since  the  concentrations  of  H-  and  OH'  are  nec- 
essarily equal  in  pure  water,  it  follows  that  [H]  =  [OH]  =  VlxlO"14, 
i.  e.,  each  ion  has  a  concentration  of  1  x  10  7.  This  means  that  water  con- 
tains approximately  1  gram  mol.  each  of  H-  and  OH'  ions,  or  1  gram 
H-  and  17  grams  OH'  ions,  in  10  7  or  10,000,000  liters.  A  consequence 
of  the  above  law  is  that  no  matter  how  much  the  concentration  of  one 
ion  is  increased  by  adding  another  substance,  the  solution  must  still 
contain  some  of  the  other  ion.  Thus,  in  acid  solutions  con.  H  •  must 
increase  and  con.  OH'  must  decrease  in  such  proportion  that  the  two 
multiplied  together  equals  about  1  x  1014.  The  H-ion  concentration  can 
he  used  therefore  to  express  the  reaction  of  neutral,  acid  and  alkaline 
solutions. 

In  place  of  water,  let  us  substitute    decinormal    hydrochloric    acid 


*The  sign  1CH4  is  simply  a  convenient  way  of  expressing  the  degree  of  dilution.  It  gives  the 
number  of  times  the  value  standing  in  front  of  it  must  be  multiplied  by  10  in  order  to  find  the 
degree  of  dilution. 


HYDROGKN-ION    CONC1NTK  ATION  27 

(0.1  N  HC1) — thai  is.  a  hydrochloric  acid  solution  containing  one  tenth 
of  the  molecular  weight  of  hydrochloric  acid  in  grams  dissolved  in  a 
liter  of  water.  At  this  dilution  IK'l  is  !)1  per  cenl  dissociated;  therefore 
the  I  lion  concentration  (or  Ch  ;is  it  is  written  lor  short)  is  0.091  JV, 
or,  in  mathematical  notation,  9.1  x  10  2. 

Method  of  Expressing  Ch.- — To  avoid  the  necessity  of  having  to  use 
several  figures  to  express  On,  as  lias  been  done  above,  Sorenson  has  intro- 
duced a  scheme  by  which  only  one  figure  is  required.  This  figure,  des- 
ignated by  Pn,  is  found  by  subtracting  from  the  power  of  ten  (i.e., 
the  figure. standing  behind  10)  the  common  logarithm  of  the  figure  ex- 
pressing the  normality  of  the  acid.*  In  a  decinormal  HC1  solution, 
therefore,  we  must  subtract  from  the  power  2,  the  common  log.  of  9.1, 
which  is  .96  (ascertained  from  logarithm  tables),  leaving  1.04.  .  Take 
another  example:  decinormal  acetic  acid  is  dissociated  only  to  the  ex- 
tent of  1.3  per  cent;  CH  is  therefore  0.0013  normal,  or  1.3  xlO3.  Since 
the  logarithm  of  1.3  is  .11,  PH  equals  3  -  .11,  or  -2.89.| 

The  only  objection  to  the  use  of  the  exponent  PH  as  an  expression  of 
the  H-ion  concentration  is  that  it  increases  in  magnitude  as  the  acidity 
becomes  less;  this  is  because  the  negative  sign  of  the  power  is  disre- 
garded. As  stated  above,  it  is  usual  to  express  the  strength  of  alkalies 
as  well  as  acids  in  terms  of  Ch,  or  PH,  because  it  is  easier  to  measure  the 
concentration  of  II  ions  than  of  OH  ions.  A  0.1  NaOH  solution  is  84 
per  cent  dissociated;  therefore  the  "OH"  ion  is  0.084  N  (i.  e.,  0.084  gram 
equivalents  OH  per  liter),  and  since  the  product  of  the  H-  and  OH' 
concentrations  must  always  equal  10  1414  (at  20°  C),  it  is  clear  that  as 
the  H  ion  increases  in  concentration,  the  OH  ion  must  reciprocally  de- 
crease. Expressed  according  to  the  above  scheme,  the  0.084  N  NaOH 
solution  gives  PH  13.06;  thus,  0.084  =  8.4  x  102;  the  log.  of  8.4  is  .924, 
and  this  subtracted  from  the  power  -2  =  1.08  as  P0h,  or  14.14  - 1.08  = 
13.06  as  PH.** 

Similarly,  PH  of  0.1  X  NH4HO  solution  is  11.286.  Its  dissociation  is 
1.4  per  cent;  therefore  the  solution  contains  only  0.0014  gram  equivalents 
HO— i.e.,  1.4  xlO-3  POH  =  3  -  0.146  =  2.854  .  • .  PH  14.14-2.854  = 
11.286.1 

'Strictly  speaking,  Pit  is  the  logarithm  to  the  base  10  of  the  concentration  of  H  ions  in  grams 
per  liter,   the  negative   sign  being   understood. 

tlf  we  wish  to  express  the  value  of  Pit  in  ordinary  notation,  we  must  find  the  antilogarithm 
of  the  difference  between  the  value  of  Ph  and  the  next  higher  whole  number;  e.  g.,  if  Ph  =  7.45, 
the  antilogarithm  of  0.55  being  3.55,  the  Ch  is  3.55  X  10"8,  or  0.000,000,0355  AT,  or  3.55  gm.  mol. 
H  ion  in  100,000,000  liters. 

**It  must  be  remembered  that  the  power  of  a  number  indicates  the  number  of  times  by  which 
that  number  must  be  multiplied  by  ten;  thus,  Ph"6  does  not  mean  that  the  H  ion  is  six  times  less 
than  Pit0,  but  1  x  10  x  10  x  10  x  10  x  10  x  10,  or  1,000,000  times  less.  Similarly,  Ph"3  is  1000  times 
as  great  as  Ph~6,  not  twice  as  great. 

A  solution  containing  almost  exactly  1  gram  molecule  of  dissociated  hydrogen  in  10,000,000  liters 
constitutes   a  neutral   solution    (Ph  =r  7). 

JThe  expressions  Ph  and  Ch  may  be  used  indiscriminately,  but  when  the  numerical  value  is 
given,  it  is  most  convenient  to  use  the  former. 


28  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

Application  of  the  Law  of  Mass  Action  in  Determining  the  Real 
Strength  of  Acids  or  Alkalies. — We  have  seen  that  it  is  the  degree  of 
dissociation  upon  which  the  real  strength  of  an  acid  depends  and  that 
this  varies  with  dilution  (page  19).  The  equilibrium  between  the  un- 
dissociated  and  dissociated  molecules  may  therefore  be  shifted  in  either 
direction  by  changing  the  concentration;  in  other  words,  the  process  of 
dissociation  is  a  reversible  reaction,  and  may  be  represented  as 
AB  ±^  A'  -\  B  \  The  law  of  ma^s  action  must  apply  in  such  a  case,  and 
as  a  matter  of  fact  it  has  been  found  that  a  constant  can  be  calculated, 
which  is  known  as  the  dissociation  constant.*  It  is  an  expression  of  the 
inherent  ability  of  the  acid  to  dissociate  into  ions,  and  is  therefore  the 
best  measure  of  the  strength  of  the  acid.  This  is  strictly  the  case  for  all 
of  the  weaker  acids,  but  strong  mineral  acids  (and  bases)  do  not  give 
a  satisfactory  constant,  so  that  the  comparison  must  not  be  made  between 
them  and  weaker  ones.  That  the  dissociation  constant  expresses  the  rela- 
tive strength  of  organic  acids  can  be  shown  by  comparing  its  value  with 
that  of  the  rate  at  which  cane  sugar  is  inverted  (see  page  23),  this  being 
proportional  to  the  concentration  of  the  II  ions  present.  K  for  some  or- 
ganic acids  is:  Acetic,  0.000018;  Formic,  0.000214;  Benzoic,  0.00006;  Sal- 
icylic, 0.00102. 

-  a~ 

The  equation  is    — — r~-    r=    K,   where   it   is  supposed   that   in  volume   V  of   the   solution   there   is 

1  gram-equivalent  of  electrolyte,  and  that  the  degree  of  dissociation  is  a;  the  quantity  of  undis- 
sociated  electrolyte  stated  in  a  fraction  of  a  gram-equivalent  will  be  la,  and  the  quantity  of  each 
ion  a.     To  illustrate,   let   us  take  acetic  acid   in   various  dilutions: 

V  a  K  x  105 

0.994  0.004  1.62 

2.02  0.00614  1.88 

15.9  0.0166  1.76 

18.1  0.0178  0.78 


CHAPTER  V 

THE  PRINCIPLES  INVOLVED  IN  THE  MEASUREMENT  OF  THE 
HYDROGEN-ION  CONCENTRATION  (Cont'd) 

THE  METHODS  OF  MEASUREMENT 

The  Electric  Method 

In  order  to  understand  the  principle  of  the  standard  method  used  for 
measuring  the  H-ion  concentration,  it  is  necessary  that  a  few  words  he 
said  concerning  the  factors  governing  the  development  of  electric  cur- 
rents in  chemical  batteries.  There  may  he  a  further  application  of  this 
knowledge  in  connection  with  the  generation  of  the  electric  currents 
which  occurs  during  physiologic  activity,  as  in  active  glands  and  muscles. 

When  a  metal  is  immersed  in  a  solution  of  one  of  its  salts,  it  has  a 
tendency  to  give  off  ions  into  the  solution.  Similar  ions  are,  however, 
already  present  in  this  solution,  and  these,  by  their  osmotic  pressure, 
tend  to  oppose  the  passage  of  the  ions  coming  from  the  metal.  The 
force  with  which  the  metal  sends  out  its  ions  into  the  solution  is  called 
the  electrolytic  solution  pressure.  If  this  is  equal  to  the  osmotic  pres- 
sure of  the  metallic  ions  in  the  solution,  there  will  he  no  electric  current 
generated,  but  if  it  is  greater  or  less  than  the  osmotic  pressure  of  the 
metallic  ion,  an  electric  current  will  he  set  up.  When  the  solution  pres- 
sure is  the  greater,  the  metal  will  become  negatively  charged,  because  its 
ions  carry  positive  charges  into  the  solution  (cations) ;  on  the  contrary, 
when  the  osmotic  pressure  is  greater  than  the  solution  pressure,  the  metal 
will  have  a  positive  charge,  owing  to  the  receipt  of  the  positive  cations 
from  the  solution. 

Because  of  a  force  called  electrostatic  attraction,  the  ions  given  off 
from  the  metal  can  not  travel  any  measurable  distance  from  the  oppositely 
charged  mass  of  metal,  so  that  from  one  of  the  electrodes  alone  it  is 
impossible  for  us  to  lead  off  any  electric  current.  For  this  purpose  we 
must  form  a  circuit.  This  is  done  in  the  manner  shown  in  Fig.  7  by 
connecting  side  tubes  coming  from  the  electrode  vessels  with  an  inter- 
mediate vessel  containing  a  solution  of  high  conductivity  and  by  con- 
necting the  metals  by  wires.  If  the  circuit  is  formed  between  the 
same  metals  in  solutions  of  the  same  concentration,  no  electric  cur- 
rent will  be   generated,   because   the   two   electrode   potentials   will   be 

29 


30 


PHYSICOCHF,MICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 


equal  and  in  opposite  directions  to  each  other.  On  the  other  hand,  should 
the  concentration  of  the  metallic  ion  in  the  solutions  be  unequal,  the 
electromotive  force  will  flow  from  the  one  electrode  to  the  other,  and 
the  pressure  with  which  it  flows  will  be  equal  to  the  difference  in  con- 
centration of  the  two  solutions.  This  is  the  principle  of  a  concentration 
cell,  and  if  we  know  the  concentration  of  one  of  the  solutions  composing 
it,  and  then  proceed  to  measure  the  electromotive  force,  we  can  obtain 
the  concentrations  of  the  other  solution  by  difference.  To  do  this  we 
must  employ  a  formula  which  takes  into  consideration  the  relation  be- 
tween the  potential  and  the  concentration  of  the  solution. 

The  potential  of  an  unknown  electrode  composed  of  a  metal  in  con- 
tact with  a  solution  of  one  of  its  salts  may  also  be  determined  by  making 
it  one  pole  of  a  battery  of  which  the  other  pole  is  composed  of  a  stand- 
ard electrode  of  unchanging  known  potential.    An  electrode  of  the  latter 


^? 


Fig.  7. — Diagram  to  show  type  of  electrodes  used  in  studying  electromotive  force.  The 
metal  in  each  electrode  is  connected  (through  a  glass  tube)  with  a  platinum  wire,  to  which 
the  apparatus  for  measurement  of  the  voltage  is  connected.  The  metal  dips  into  a  solution 
contained  in  the  electrode  vessel  and  tilling  the  side  tube.  The  latter  dips  into  an  inter- 
mediate vessel  containing  saturated  KG  solution.  The  currents  flow  through  the  circuit  under 
the  following  conditions:  (1)  dissimilar  metals  dipping  into  the  same  fluid;  (2)  similar  metals 
dipping    into    different    fluids;    (3)    dissimilar   metals    dipping    into    different    fluids. 

type  can  most  readily  be  made  by  bringing  pure  mercury  in  contact 
with  a  saturated  solution  of  calomel  (Hg2Cl2)  in  normal  potassium  chlo- 
ride solution.  Under  suitable  conditions  (i.  e.,  when  the  circuit  is  com- 
pleted), a  potential  of  +0.560  v.  is  developed  in  this  so-called  caloim  I 
electrode*— that  is,  positive  ions  of  mercury  are  deposited  on  the  mercury 
from  the  calomel  solution  at  this  pressure.  Suppose  that  we  connect  a 
calomel  electrode,  through  the  intermediation  of  some  solution  which 


*The  calomel  electrode  consists  of  a  suitably  shaped  class  vessel  containing  pure  mercury,  con- 
nected by  means  of  a  platinum  wire  with  a  conductor,  and  filled  with  a  saturated  solution  of  pure 
mercurous  chloride  in  normal  KC1  solution  up  to  such  a  level  that  it  also  fills  a  side  tube  connected 
with  a  vessel  containing  a  saturated  solution  of  potassium  chloride.  Into  this  vessel  also  runs  a 
similar  side  tube  from  the  unknown  electrode.  By  having  an  excess  of  undissolved  calomel  in  the 
solution  in  the  calomel  electrode  its  saturated  condition  is  maintained  during  the  chemical  changes 
which  accompany  the  production  of   the   electric  current. 


HYDROGEN   [ON    CONCENTR  \TI<>\ 


:;i 


will  serve  ;is  ;i  good  conductor,  with  another  electrode,  tli<'  two  elec- 
trodes being  also  connected  by  wires  with  electrical  apparatus  Eor 
measuring  the  total  potential  of  the  battery;  then  by  adding  +  0.560  v. 
to  or  subtracting  this  value  from  the  total  potential  (depending  on  the 
sign  of  the  unknown  electrode)  Ave  can  tell  the  potential  of  the  unknown 
electrode. 

We  have  discussed  these  principles  of  electrochemistry  because  they 
form  the  basis  upon  -which  depends  the  standard  method  for  the  deter- 
mination of  the  H-ion  concentration  of  fluids.  Suppose,  for  example, 
that  in  place  of  using  a  metal  in  the  construction  of  one  electrode,  we 
use  an  electrode  consisting  of  a  layer  of  pure  hydrogen  gas  in  contact 
with  a  solution  in  which  are  free  II  ions;  then  the  rate  at  which  H  ions 


t&L- 


Fig.  8. — Diagram  of  apparatus  for  the  measurement  of  the  H-ion  concentration.  The  cur- 
rent generated  in  the  battery  (composed  of  calomel  electrode,  connecting  vessel  with  KC1  solu- 
tion, and  the  H  electrode)  or  that  from  the  normal  element  is  transmitted  through  a  reversing 
key  to  the  bridge  wire,  where  the  voltage  is  compared  with  a  steady  current  flowing  through  the 
bridge  wire  from  an  accumulator.  The  capillary  electrometer  is  used  to  detect  the  flow  of 
current  at  various  positions  of  the  movable  contact  on  the  bridge  wire.  (Modified  from 
Sorensen.) 


become  added  to  the  solution  from  the  H  layer,  or  taken  from  it,  will  de- 
pend on  the  concentration  of  H  ions  in  solution.  In  order  to  secure  a 
hydrogen  electrode  fulfilling  the  above  requirements,  it  is  necessary  to 
employ  some  means  by  which  a  layer  of  hydrogen  may  be  furnished,  and 
fortunately  this  can  be  done  by  taking  advantage  of  the  property  which 
spongy  platinum  possesses  of  absorbing  large  quantities  of  this  gas.  It 
is  also  necessary  to  keep  an  atmosphere  of  pure  II  in  contact  Avith  the 
fluid. 

As  is  the  case  of  the  simpler  cells  described  above,  there  are  two 
types  which  we  might  use  for  measuring  the  electromotive  force  gen- 
erated in  the  unknown  electrode:  a  concentration  cell  composed  of  two 


32  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESS  1 38 

hydrogen  electrodes,  of  which  one  contains  a  solution  of  known  H-ion 
concentration,  and  the  other  the  solution  in  which  this  is  unknown; 
and  a  cell  of  which  one  electrode  is  a  standard  calomel  electrode  and 
the  other,  a  hydrogen  electrode  containing  the  unknown  solution. 

The  exact  arrangement  of  the  apparatus  in  which  the  calomel  elec- 
trode is  used  will  be  seen  in  the  accompanying  sketch.  The  hydrogen 
electrode,  it  will  be  noticed,  is  a  very  small  V-shaped  tube,  in  which  is 
suspended  a  platinum  wire  coated  with  spongy  platinum  and  dipping 
into  a  solution  which  nearly  fills  the  tube.  The  space  above  the  solution 
is  filled  with  pure  hydrogen.  This  and  the  calomel  electrode  are  con- 
nected with  suitable  electric  measuring  instruments,  and  the  circuit  is 
completed  by  connecting  the  two  electrodes  by  means  of  an  intermediate 
vessel  containing  a  saturated  solution  of  potassium  chloride.  This  con- 
necting solution  is  used  because  it  has  been  found  that  the  electric  cur- 
rents set  up  at  the  contact  between  different  solutions  are  so  small  that 
they  can  be  disregarded.* 

As  outlined  above,  the  hydrogen  electrode  is  that  which  is  used  to 
determine  the  TT-ion  concentration  of  blood,  the  particular  point  about 
it,  in  comparison  with  the  apparatus  used  for  simpler  solutions,  being 
that  the  hydrogen  is  not  changed  in  the  course  of  the  experiment.  This 
precaution  is  to  prevent  the  carbon  dioxide  of  the  blood  from  being 
"washed  out"  of  it  by  a  frequently  changing  atmosphere  of  hydrogen. 
Many  inaccuracies  in  the  earlier  results  obtained  by  this  method  were 
due  to  the  removal  of  carbon  dioxide,  which,  as  we  shall  see  later,  is 
one  of  the  chief  acids  contributing  to  the  Il-ion  concentration  of  blood. 

The  Indicator  Method 

As  pointed  out  in  a  previous  chapter  (page  22),  the  method  of  titra- 
tion for  acidity  or  alkalinity  in  which  a  standard  solution  of  alkali  or 
acid  is  added  until  a  certain  change  in  the  color  of  a  suitable  indicator 
is  detected,  does  not  afford  any  information  regarding  the  Il-ion  con- 
centration actually  present  in  the  solution.  It  tells  us  the  total  con- 
centration of  available  acid  or  base,  both  dissociated  and  undissociated. 
By  modification  of  the  method  of  procedure,  however,  we  may  also  use 
indicators  for  determining  the  H-ion  concentration.  The  principle  of 
this  method  depends  on  the  fact  that  there  are  certain  dyes  which 
change  quite  distinctly  in  tint  with  very  slight  changes  in  the  Il-ion 
concentration,  so  that  if  we  use  dyes  which  possess  this  property  at  a 
point  near  that  of  neutrality  (i.e.,  between  PH6.5  and  PH8),  we  can  es- 


*A  description  of  the  technic  for  measuring  the  electric  potential  developed  by  the  cell  would 
be  out  of  place  here.  Suffice  to  say  that  the  strength  of  the  current  is  compared  with  that  of  a 
current  of  known  strength  furnished  by  a  normal  cell,  the  comparison  being  made  by  a  bridge  wire 
F,  a  capillary  electrometer  II   being  employed  to  detect  the  direction  and  degree  of  current. 


HYDROGEN-ION    CONCENTRATION' 


33 


t'nnate  the  H-ion  concentration  of  the  body  fluids  with  very  remarkable 
accuracy,  provided  certain  precautions  are  taken  to  circumvent  the 
disturbing  influence  which  the  protein  and  salts  in  these  fluids  may  have 
on  the  color  change. 

To  understand  this  use  of  indicators,  it  is  important  to  bear  in  mind 
that  one  solution  reacting  neutral  to  one  indicator  may  have  a  H-ion 
concentration  which  differs  very  markedly  from  that  of  another  solu- 
tion reacting  neutral  to  another  indicator.  This  is  because  indicators 
react  to  different  H-ion  concentrations.  A  solution  that  is  neutral  to 
phenolphthalein  has  a  PH  of  about  9,  whereas  one  neutral  to  methyl  or- 
ange has  a  PH  of  about  4.  This  can  be  very  clearly  shown  by  titrating 
a  solution  of  phosphoric  acid  with  decinormal  alkali.  After  a  certain 
amount  of  alkali  has  been  added  it  will  be  noticed  that  methyl  orange 
changes  from  red  to  yellow,  but  after  it  has  changed  and  is  therefore 
alkaline  as  judged  by  this  indicator,  it  still  remains  distinctly  acid  to- 
wards phenolphthalein  (shows  no  red  tint)  even  though  considerably 
more  alkali  is  added.  The  methyl  orange  is,  therefore,  itself  unrespon- 
sive to  weak  acids  such  as  remain  after  the  greater  part  of  the  phos- 
phoric acid  has  been  neutralized  by  the  alkali. 

The  series  of  indicators  which  has  been  employed  for  this  purpose  is 
given  in  the  accompanying  table,  along  with  the  PH  limits  through  which 
they  change  in  color. 

List  op  Indicators 


COMMON 

CONCEN- 

COLOR 

RANGE 

CHEMICAL  NAME 

NAME 

TRATION 

CHANGE 

Pn 

Thymol  sulfon   phthalein 

per  cent 

(acid  range) 

Thymol  blue 

0.04 

Red-yellow 

1.2-2.8 

Tetra  bromo   phenol   sul- 

fon phthalein 

Brom  phenol 

blue 

0.04 

Yellow-blue 

3.0-4.6 

Ortho  carboxy  benzene 

azo  di  methyl 

aniline 

Methyl  red 

0.02 

Red-yellow 

4.4-6.0 

Ortho  carboxy  benzene 

azo  di  propyl 

aniline 

Propyl  red 

0.02 

Red-yellow 

4.8-6.4 

Di  bromo  ortho  cresol 

sulfon  phthalein 

Brom  cresol 

purple 

0.04 

Yellow- 
purple 

5.2-6.8 

Di  bromo  thymol  sulfon 

Brom  thymol 

phthalein 

blue 

0.04 

Yellow-blue 

6.0-7.6 

Phenol  sulfon  phthalein 

Phenol  red 

0.02 

Yellow-red 

6.8-8.4 

Ortho   cresol  sulfon 

phthalein 

Cresol  red 

0.02 

Yellow-red 

7.2-8.8 

Thymol   sulfon   phthalein 

Thymol  blue 

0.04 

Yellow-red 

8.0-9.6 

(see  above) 

Ortho   cresol   phthalein 

Cresol 

phthalein 

0.02 

Colorless-red 

8.2-9.8 

These   dyes  may   now  be   obtained   in   this   country. 


(W.  M.  Clark  and  H.  A.  Lubs.)» 


34  PHYSICOCHEMICAL   BASIS   OP    PHYSIOLOGICAL   PROCESSES 

Briefly  stated  the  method  for  measuring  the  II-ion  concentration  con- 
sists in  preparing  a  series  of  solutions  containing  known  concentrations 
of  H-ion — that  is  to  say,  of  known  PH — and  adding  to  each  solution  an 
equal  amount  of  an  indicator  which  exhibits  easily  distinguishable 
changes  in  tint  at  H-ion  concentrations  approximating  those  believed 
to  be  present  in  the  unknown  solution.  The  same  indicator  is  added  to 
the  unknown  solution,  which  is  then  placed  side  by  side  with  the  stand- 
ards to  find  Avith  which  of  them  it  most  closely  matches.  The  series 
of  solutions  of  known  H-ion  concentration  is  prepared  by  mixing  fif- 
teenth normal  solutions  of  Na2HP04  and  KH2P04  in  varying  propor- 
tions as  given  in  the  following  table: 

Preparation   of   Standard  Solutions 
The   solutions   are   mixed   in   the   proportions   indicated   below   to   obtain    the   desired    Ph:* 

Ph  6.4      6.6      6.8       7.0      7.1       7.2      7.3      7.4       7.5       7.6      7.7      7.8      8.0      8.2      8.4 

Primary    Potas.  73       63        51        37        32        27       23        19        15.8     13.2     11  88       5.6      3.2      2.0 

Phos.,  c.c. 
Secondary    Sodium    27        37        49        63        68        73        77       81        84.2    86.8    89        91.2    94.4    96.8    98.0 

Phos.,   c.c. 

(From   Levy,    Rowntree  and  Marriott.) 

*Standard    phosphate   mixtures   are   prepared    according   to    Sorensen's   directions   as    follows: 
1/15    mol.    acid    or    primary    potassium    phosphate. — 9.078    grams    of    the    pure    recrystallized    salt 
(KlUI'Oj)    are   dissolved   in   freshly   distilled   water   and   made   up    to    1    liter. 

1/15  mol.  alkaline  or  secondary  sodium  phosphate. — The  pure  recrystallized  salt  ( XaJTP04 .  12HoO) 
is  exposed  to  the  air  for  from  ten  days  to  two  weeks,  protected  from  dust.  Ten  molecules  of  water 
of  crystallization  are  given  off  and  a  salt  of  the  formula!  Nao]  1  P<  >i  .  _'l  !•_•<  )  is  obtained;  11.876  grams 
of  this  are  dissolved  in  freshly  distilled  water  and  made  up  to  1  liter.  The  solution  should  give  a 
deep  rose  red  color  with  phenolphthalein.  If  only  a  faint  pink  color  is  obtained,  the  salt  is  not 
sufficiently  pure. 

The  indicator  method  is  extremely  accurate  when  used  with  pure 
solutions  of  acids,  but,  as  mentioned  above,  it  is  apt  to  be  inaccurate,  at 
least  with  most  indicators,  when  protein  or  inorganic  salts  are  pres- 
ent in  the  solution,  and  of  course  it  is  quite  unusable  with  colored 
fluids  such  as  blood.  In  order  to  overcome  these  difficulties,  the 
dialysis  method  has  recently  been  evolved.  It  consists  in  placing  the 
fluid — blood,  for  example — in  a  dialyser  sac  composed  of  celloitlin  and 
about  as  large  as  a  small  test  tube.  The  sac  is  placed  in  a  wider  test 
tube  of  hard  glass  containing  an  isotonic  solution  of  sodium  chloride 
that  has  been  carefully  tested  to  ascertain  that  it  is  strictly  neutral. 
The  amount  of  blood  or  serum  required  for  this  method  is  only  2  or 
3  c.c,  and  the  amount  of  salt  solution  placed  outside  the  sac  should  be 
about  the  same.  It  takes  only  from  five  to  ten  minutes  for  dialysis  to 
occur.  The  celloidin  sac  is  then  removed,  a  few  drops  of  the  indicator 
are  thoroughly  mixed  with  the  dialysate,  and  the  tube  compared  with 
the  series  of  standards  until  the  corresponding  lint  is  matched.  This 
indicates  the  H-ion  concentration  in  the  dialysate.  The  tints  produced 
by  using  snlphonephenolphthalein  are  reproduced  as  nearly  as  possible 


P„  7-0 


Ph  7-1 


Ph  7-2 


Ph7-3 


10 


~~x 


u 


PH  7-fr 

D 


www 


P„7-5  P„7-6  PBr-7  P„7-8  P„S-0 


Fig-  9. — Chart  showing  approximately  the  tints  produced  by  adding  sulphophenolphthalein  to  a  series 
of  phosphate  solutions  of  the   H-ion  concentrations  indicated  in  each  case  by   Ph. 


lIV|)KO(il',NT-lON    CONCENTRATION 


::: 


in  the  accompanying  chart.  The  Il-ion  concentration  of  the  unknown 
solution  is  that  of  the  tint  with  -which  it  matches  in  the  series. 

It  might  be  thought  thai  this  met  hod  would  be  inaccurate  because  of 
the  loss  of  carbon  dioxide  from  the  blood.  By  actual  experiment,  how- 
ever, it  has  been  found  that,  if  the  blood  is  collected  with  certain  pre- 
cautions, the  error  is  negligible.  The  method  is,  therefore,  a  most  useful 
one  clinically. 

The  following  table  gives  the  hydrogen-ion  concentration  or  true 
reaction  of  the  body  fluids. 


i-ii 


Ph 


Muscle  juice  (fresh  ) 
Muscle  juice  (autolyzed) 
Pancreas  extract 
Peritonea]  fluid 
Pericardial  fluid 
Aqueous  humor 
Vitreous  humor 
Cerebrospinal  fluid 
Cerebrospinal  fluid 
Amniotic  fluid 
Amniotic  fluid 
Milk  (human) 
Milk  (cow) 
Milk  (goat) 
Milk  (ass) 

(W.  M.  Clark  and  H. 


Blood  7.4 

Urine  6.0 

Saliva  6.9 

Gastric  juice  (adult)  0.9-1.6 

Gastric  juice  (infant)  5.0 

Pancreatic  juice  (dog)  S.3 

Small  intestinal  contents  8.3 
Small  intestinal  contents   (infant)       3.1 

Bile  from  liver             .  7.8 

Bile  from  gall  bladder  5.3-7.4 

Perspiration  7.1 

Perspiration  4.5 

Tears  7.2 


6.8 
Variable 

5.6 
7.4 
7.4 
7.1 
7.0 
7.2 
8.3 
7.1 
8.1 
7.0-7.2 
6.G-6.8 
6.6 
7.6 


A.  Lubs.) 


CHAPTER  VI 

THE    REGULATION    OF   NEUTRALITY   IN    THE   ANIMAL   BODY 

AND  ACIDOSIS 

Nothing  is  more  constant  in  the  animal  economy  than  the  H-ion  con- 
centration (CH)  of  the  fluids  which  bathe  the  tissues.  This  regulation 
is  fundamentally  of  a  physicochemical  nature,  depending  on  the  inter- 
action of  alkalies  with  acids,  of  which  carbonic  and  phosphoric  acids 
and  the  proteins  are  the  most  important.*  When  different  amounts  of 
acids  or  alkalies  are  added  to  water,  the  range  of  variation  in  II  ion  is 
very  extensive,  whereas  in  blood  the  range  is  very  limited  indeed,  not 
extending  beyond  PH7  and  PH7.52  (i.  e.,  CH  never  goes  above  that  of  a 
0.000,000,1  N  solution  or  below  that  of  a  0.000,000,03  N  solution).  In 
other  words  blood  can  withstand  considerable  additions  of  acid  or  al- 
kali without  much  change. 

Buffer  Substances. — The  chemical  reactions  upon  which  this  remark- 
able constancy  in  reaction  depends  have  been  explained  by  Lawrence 
J.  Henderson.10     The  fundamental  equations  are  as  follows: 

M.HPO,  +  IT  A  —  MH,P04  4  MA,  and 
MHCO,  +  HA  =  H2CO,  4  MA, 
when  M  =  a  basic  radicle,  and  A,  an  acid  radicle. 

Now  it  has  been  discovered  that  weak  acids,  like  carbonic  and  phos- 
phoric, possess  the  remarkable  property  of  maintaining  the  reaction 
constant  when  they  are  present  in  a  solution  which  also  contains  an 
excess  of  their  salts.  Under  these  circumstances  the  concentration  of 
ionized  hydrogen  is  almost  exactly  equal  to  the  product  of  the  dissocia- 
tion constant t  of  the  acid  (see  page  10)  multiplied  by  the  ratio  be- 
tween free  acid  and  salt;  in  other  words,    . 

[HA] 
If  carbonic  acid  is  present  in  a  solution  of  bicarbonates  so  that  there 


*  According  to  circumstances,  proteins  may  act  either  as  acids  or  as  alkalies.  They  are  there- 
fore  called   amphoteric. 

fThe  ionization  constant  has  already  been  referred  to  as  a  figure  which  expresses  the  tendency 
of  a  weak  acid  or  base  to  dissociate  in  an  aqueous  solution.  "It  expresses  the  proportion  in  which 
the  nondissociated  part  is  capable  of  existing  in  the  presence  of  its  ions,"  and  therefore  is  a  gauge 
of  the  strength.  The  dissociation  constant  amounts  to  about  0.000,000,5  for  carbonic  acid;  that  is, 
the  dissociation  of  H0CO3  into  H'  +  HCO?/  at  room  temperature  will  be  such  that  the  concentra- 
tion of  H-ion  equals  a  0.000,000,5  N  solution. 

36 


MIDOSIS  37 

arc  equivalent  quantities  of  fra  II.,C03  and  bicarbonate — i.e.,   L..,  =— 

— the  II-ion  concentration  will  be  exactly  the  same  as  the  dissociation 
constant  of  carbonic  acid;  therefore  0.000,000,5  N  (PH  =  6.31),  or  about 
five  times  the  value  of  neutrality,  0.000,000,1  N  (P„  =  7.31).  If  ten 
times  as  much  free  carbonic  acid  as  bicarbonate  is  present,  then  the  II-ion 

concentration   will   be   fifty   times   that   of   neutrality,    i.e. ,-....  =-=- 

x  0.000,000,5  —  0.000,005  (P„  =  5.31);  if  there  is  ten  times  less  carbonic 
acid  than  bicarbonate,  the  II-ion  concentration  will  be  one-half  that  of 

neutrality,  i.  e.,  4Ittt=  TR><  0.000,000,5  =  0.000,000,05)  (PH  =  7.31)  ;  or 
[r>AJ         ID 

if  twenty  times  less,  one  fourth  (PH  =  7.6).  Since  a  large  amount  of 
bicarbonate  is  actually  present  in  blood  (enough  to  yield  from  50  to  65  c.c. 
C02  per  100  c.c.  of  blood)  (sec  page  391),  and  the  free  carbonic  acid 
undergoes  fluctuations  which  are  only  trivial  when  compared  with  those 
which  have  been  chosen  in  the  above  examples,  it  is  clear  that  there  must 
be  very  little  change  in  the  H-ion  concentration  of  the  blood  in  comparison 
with  the  variations  which  would  occur  were  no  bicarbonate  present. 

Another  weak  acid  which  acts  like  carbonic  in  maintaining  neutral- 
ity is  acid  phosphate  (MH2P04),  and  for  the  same  reason — namely,  that 
its  dissociation  constant  is  of  similar  magnitude  to  the  H-ion  concen- 
tration. Although  the  blood  plasma  itself  contains  much  less  phosphate 
than  bicarbonate,  the  tissues  contain  a  considerable  amount,  which  en- 
ables them  to  maintain  their  neutrality.  This  action  of  bicarbonates  and 
phosphates  is  styled  the  buffer  action,  meaning  that  it  serves  to  damp 
down  the  effect  on  the  H-ion  concentration  which  additions  of  acids  or 
alkalies  would  otherwise  have.  As  pointed  out  by  Bayliss,  however,  a 
better  word  to  use  would  be  "tampon  action,"  since  the  substances 
actually  soak  up  much  of  the  added  H-  or  OH'  ions.  It  is  not  confined 
to  the  fluids  of  the  higher  animals,  but  is  very  widely  distributed 
throughout  nature ;  for  example,  in  the  ocean  and  in  the  fluids  of  marine 
organisms  and  animalcules  (see  L.  J.  Henderson).11 

Although  the  actual  reaction  by  which  neutrality  is  maintained  is 
purely  of  a  physicochemical  nature,  some  provision  must  obviously  be 
made  so  that  the  acid  and  basic  substances  that  take  part  in  it  may  be 
supplied  and  those  produced  by  the  reactions  removed  as  occasion  re- 
quires. The  source  of  supply  is  partly  exogenous  and  partly  endogenous. 
The  exogenous  source  is  the  basic  and  acid  substances  present  in  the 
food;  and  although  we  do  not  ordinarily  attempt  to  control  the  amounts 
of  these  substances  ingested,  we  may  do  so,  as,  for  example,  by  the 
persistent  administration  of  soda  in  cases  of  pathologic  acidosis.  The 
endogenous  source  depends  on  the  constant  production  in  metabolism 


38  PHYSICOCHEMICAL    BASIS   OF   PHYSIOLOGICAL   PROCESSES 

of  acids  such  as  carbonic,  phosphoric,  lactic,  and  sulphuric,  and  of 
alkalies  such  as  ammonia.  Amphoteric  substances,  like  amino  acids  and 
proteins,  may  functionate  either  as  acids  or  as  alkalies.  Whatever  may 
be  its  source,  a  considerable  reserve  of  alkali  is  undoubtedly  available 
in  the  animal  organism.  This  required  store  of  alkali  appears  to  be 
automatically  liberated  as  a  result  of  the  physicochemical  process. 

The  removal  is  affected  by  three  pathways:  (1)  through  the  lungs 
gaseous  carbonic  acid  is  eliminated;  (2)  through  the  kidneys,  the  fixed 
acids;  and  (3)  through  the  intestines,  some  of  the  phosphoric  acid. 

Carbonic  acid  is  produced  in  large  amounts  in  the  normal  process  of 
metabolism,  and  is  excreted  in  a  gaseous  condition  by  the  lungs.  Varia- 
tion in  its  excretion  is  the  most  important  mechanism  for  controlling 
temporary  changes  in  CH.  In  order  to  make  this  clear,  it  may  bo  well  to 
revert  for  a  moment  to  the  physicochemical  equation  by  which  carbonic 
acid  is  enabled  to  maintain  neutrality.     This  may  be  written:     CH  = 

tt  p/~\ 

molecular  ratio   _,  JL~  *  •  .    The  ratio  mav  be  increased  either  bv  adding 
.Villi  O, 

free  carbonic  acid  to  the  blood  fas  by  causing  an  animal  to  respire  some 
of  the  gas),  or  by  the  addition  of  some  other  acid  (e.  g.,  oxybutyric,  as  in 
diabetes)  which  will  decompose  some  of  the  NaHC03  and  produce 
H2C03.  The  increase  which  these  changes  would  cause  in  CH  of  the 
blood  is  prevented  by  the  remarkable  sensitivity  of  the  respiratory  cen- 
ter to  changes  in  CH.  An  increase  which  is  much  less  than  can  be 
measured  by  physicochemical  means  stimulates  the  center,  causing  in- 
creased pulmonary  ventilation,  so  that  the  carbonic  acid  is  immediately 
eliminated  through  the  lungs.  This  elimination  does  not  stop  when  the 
old  level  of  carbonic-acid  concentration  is  reached,  but  proceeds  until 

TT    pQ 

the  original  ratio    ^T  t^A    is   again  attained  in  the  blood,  and  CH  is 
NaHCO, 

restored  exactly  to  its  original  value.  If  it  stopped  at  the  old  CO.,  con- 
centration, the  ratio  would  be  too  high  because  there  is  less  NaHC03. 

THE  THEORY  OF  ACIDOSIS 

Although  these  considerations  indicate  that  variations  may  occur  in 
the  bicarbonate  content  of  the  blood  without  any  significant  change  in 
CH,  they  also  show  that  the  bicarbonate  content  must  be  a  criterion  of 
the  acid-base  balance  of  the  blood,  and  probably  of  the  body  fluids  in 
general.  As  pointed  out  by  Van  Slyke,12  bicarbonate  represents  the  ex- 
cess of  base  which  is  left  over  after  all  the  fixed  acids  have  been  neu- 
tralized. It  represents  the  base  that  is  available  for  the  neutralization  of 
any  excess  of  such  acids  that  may  appear — a  measure  of  the  reserve  of 
"buffer  substance"  or,  more  specifically,  the  alkaline  reserve  of  the  body. 


acidosis  :;ii 

Under  norma]  conditions  the  amounl  of  NaHCOa  in  blood  plasma  is  very 

constanl  (amounting  tit  50-65  vols,  per  cent  C02),  and  when  it  is  reduced, 

it  indicates  thai  an  excess  of  fixed  acid  must  be  present.    This  is  taken 

by  Van  Slyke  and  others  to  constitute  the  real  definition  of  acidosis 

namely,  "a  condition  in  which  the  concentration  of  bicarbonate  in   the 

blood  is  reduced   below  the  normal   level."     II'  the   respiratory   center 

for  any  reaso.11  should  nol    respond   promptly  enough   to  an   increase   in 

H,COa 
the  molecular  ratio         urn    '  ;m<^     H  eonseQuelltly  become  greater,  the 

condition  is  called  uncompensated  acidosis,  bu1  if  the  center  does  respond 
so  that  (\i  is  held  constant  (although  XalK'O.  is  decreased),  the  condition 
is  one  of  compensated  acidosis. 

For  practical  reasons,  therefore,  the  study  of  pathologic  acidosis  de- 
pends on  an  estimation  of  the  bicarbonate  content  of  the  blood  or,  since 
it  is  simpler  to  carry  out  and  is  of  equal  value,  of  the  plasma.  When 
plasma  is  obtained  by  removing  blood  from  a  vein  of  the  aim  and  cen- 
trifuging  immediately  out  of  contact  with  air  (so  that  C02  may  not  be 
lost  from  it)  it  contains  approximately  60  vols,  per  cent  of  C02.  Since 
we  know  that  the  partial  pressure  of  C02  in  blood  is  equal  to  42  mm.  Hg 
(ascertained  from  determinations  of  the  alveolar  C02)  (see  page  •544), 
we  can  calculate  how  much  of  the  60  vols,  per  cent  must  be  in  simple 
solution  by  application  of  the  law  of  solution  of  gas  in  a  liquid  (page 
336).     It  has  been  found  that  plasma  at  body  temperature  and  at   760 

mm.  Hg  (atmospheric  pressure)  dissolves  0.54  per  cent  C02,  so  that  at 

42 

42  mm.  it  will  dissolve         -x  100x0.54  =  3  vols,  per  cent.    Transcribing 

[H2C03]  3  1 

the  figures  to  our  equation  we  get =  — ,  or  ■ — .* 

[NaHC03]      60         20 
This  definition  of  acidosis  leaves  out  of  regard  all  conditions  that  may 

tt  ri(") 

raise  the  ratio  -T  JL^'J  bv  the  addition  of  H.,C03  without  decomposing 

NalK  03    ' 
any  of  the  NaHC03,  such,  for  example,  as  occurs  when  an  excess  of  free 

carbonic  acid  is  present  in  the  blood  plasma.  Since  increases  in  free 
C02  are  not  infrequent  in  both  health  and  disease — e.  g.,  asphyxial  con- 
ditions— the  above  definition  is  not  sufficiently  comprehensive.  When 
we  come  to  study  the  control  of  the  respiratory  center,  we  shall  see  that 

H  CO 

an  increase  in  the   ratio  ^r-' _,_  -  of   sufficient   magnitude   to   cause   an 

NaHC03 
actual  increase  in  CH  can  be  produced  by  causing  an  animal  to  respire  air 


*This   agrees    sufficiently    with    the    result    as    calculated    from    the   known    values   of   the   equation 
=  H    .      Thus,    if    we    take    Cn    as    0.35  x  10'7,    X    as    0.605    for    blood    conditions,    and 


NaHCOa    —       K 

k-            .    .       ,n  -    ar    u      ,•           a    t,         i                    ■      H0CO3  0.605  X  0.35  X  1Q--    _       1 

J\   a.s  4,4  x  10"'    (Michaelis   and    Rona),,  we   get     .   ..,,„     =  r-; r-rr- —  ttt 

AallLUj  4,4  X  1"  4\ 


40  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

containing  an  excess  of  C02 — a  true  acidosis,  but  one  for  which  no  place 
is  found  in  the  above  definition. 

Nevertheless,  Van  Slyke's  definition  has  a  real  value,  because  it  em- 
phasizes the  importance  of  a  determination  of  the  bicarbonate  as  a  cri- 
terion of  the  degree  of  the  forms  of  acidosis  usually  met  with  in  disease. 
The  bicarbonate  under  such  conditions  may  become  reduced  either  be- 
cause of  the  appearance  of  improperly  oxidized  fatty  acids,  like  /?-oxy- 
butyric  and  acetoacetic,  when  carbohydrate  metabolism  is  upset  as  in 
diabetes  or  starvation,  or  because  the  acids  produced  by  a  normal 
metabolism  are  inadequately  eliminated  by  the  kidneys,  as  in  nephritis. 

Accordingly,  if  the  respiratory  mechanism  and  increased  mass  move- 
ment of  the  blood  (for  an  increase  in  CH  accelerates  this  also)   should 

TT  CO 
fail  to  eliminate  C0o  quickly  enough  so  as  to  keep  the       Jt~  J*  ratio  at 

JNaxi003 

one  twentieth,  then  CH  will  rise.     This  is  not  likely  to  happen  until  a 

large  part  of  the  NaHC03  has  been  used  up,  so  that  an  estimation  of  that 

actually   present   must    be    a    reliable    index    of   the    proximity   to    this 

condition. 

A  sustained  increase  in  CH  is  incompatible  with  life.     The  NaHC03  is 

the  buffer,  the  factor  of  safety  which  prevents  its  occurrence.    Although 

it  is  only  in  arterial  blood  (i.e.,  after  elimination  of  excess  of  002  by 

TT  00 
the  lungs  has  been  accomplished)   that  constancy  in  the  ratio        ImA 

JNariOO., 

can  be  expected,  it  is  fortunate,  for  practical  reasons,  that  venous  blood 
collected  during  muscular  rest  and  without  stasis  should  be  only  slightly 
different. 

When  acids  are  added  to  the  blood,  they  will  first  of  all  be  neutralized 
by  the  "buffers"  of  the  plasma — namely,  NaHC03  and  protein,  as  we 
have  seen.  But  this  is  only  the  first  line  of  defense  against  acidosis,  for 
buffer  substances  present  in  the  corpuscles  may  also  be  used.  This  intra- 
corpuscular  reserve  of  alkali  is  mobilized  partly  by  transference  of  K 
and  Na  from  corpuscle  to  plasma,  but  mainly  by  that  of  HC1  from  the 
plasma  into  the  corpuscle,  so  releasing  base  in  the  former  to  combine 
with  the  added  acid  (e.  g.,  H2C03),  according  to  the  equation: 
H,C03  +  NaCl  +±  NaHC03  +  HOI.  The  HOI  on  entering  the  corpuscle 
reacts  with  phosphates  according  to  the  equation:  HC1  +  Na2HP04  *=> 
NaH2P04  +  NaCl.  This  is  a  particularly  important  detail  of  the  buffer 
action  of  the  blood,  for  it  shows  us  how  the  phosphates  of  the  corpuscles 
are  rendered  available  for  neutralizing  acids  added  to  the  plasma,  where 
there  are  practically  no  phosphates.  Indeed  the  transference  of  acid 
through  the  corpuscular  envelope  indicates  that  the  same  sort  of  thing 
must  go  on  with  the  other  cells  of  the  body,  so  that  the  plasma,  itself 
rather  poor  in  buffer  substances,  has  all  those  of  the  body  at  its  disposal. 


ACIDOSIS  41 

THE  MEASUREMENT  OF  THE  RESERVE  ALKALINITY 

1.  Titration  Methods 

There  are  several  methods  by  which  the  restive  alkalinity  of  the  blood 
may  be  measured.  The  simplest  in  theory  consists  in  seeing  how  much 
standard  acid  must  be  added  to  a  measured  quantity  of  blood  plasma  in 
order  to  reach  the  neutral  point  as  judged  by  change  in  tint  of  some 
indicator.  The  indicators  employed  (e.  g.,  methyl  orange)  are  such  as 
change  their  tints  at  II-ion  concentrations  that  are  well  to  the  acid  side 
of  neutrality  (i.  e.,  at  a  high  Ch  or  low  PH).  To  bring  the  plasma  to  this 
point  of  neutrality  the  added  alkali  will  need  to  neutralize,  not  only  the 
bicarbonate  of  the  plasma,  but  other  acid-binding  substances  as  well. 
This  will  give  us  a  false  impression  of  the  acid-binding  powers  of  the 
plasma,  since,  at  the  normal  CH  of  the  blood,  proteins  do  not  absorb  acids 
to  anything  like  the  extent  they  do  at  higher  degrees  of  CH.  Another 
objection  to  the  method  is  that  the  proteins  interfere  with  the  sensitive- 
ness of  the  indicators. 

The  objections  can  be  removed  by  determining  the  end  point  electro- 
metrically  or  by  indicators  that  change  tint  at  about  PH7.  The  most 
practical  way  is  to  determine  the  change  in  CH  produced  by  adding  a 
known  volume  of  standard  acid  to  blood  plasma.  The  resulting  change 
in  CH  will  then  be  greater  the  less  the  alkaline  reserve.  In  the  electro- 
metric  method  irregularities  that  might  be  caused  by  variable  amounts 
of  carbonic  acid  in  the  blood  to  start  with  are  best  controlled  by  removing 
the  C02  from  the  plasma  after  adding  the  standard  acid.  The  procedure 
therefore  consists  in  mixing  1  c.c.  plasma  with  2  c.c.  N/50  HC1  in  a  small 
separating  funnel,  which  is  then  evacuated  so  as  to  remove  the  C02, 
after  which  the  fluid  is  transferred  to  a  hydrogen  electrode  and  Ch 
measured  (see  page  29).  In  normal  blood  this  should  be  10  n-6  (PH5.6). 
In  acidosis,  where  there  is  a  depleted  alkaline  reserve,  the  2  c.c.  of  acid 
will  cause  a  much  greater  change  in  CH — in  diabetic  blood  to  below  5 
or  lower. 

The  technic  involved  in  the  above  method  is,  however,  too  exacting  for 
routine  clinical  work.  For  such  purposes  the  colorimetric  method  of  Levy 
and  Rowntree  may  be  employed. 

The  Method  of  Levy  and  Rowntree.13 — A  test  tube  made  of  hard 
("nonsol")  glass  of  about  20  c.c.  capacity,  containing  about  a  gram  of 
powdered  neutral  potassium  oxalate,  is  filled  with  newly  drawn  blood, 
immediately  stoppered  and  placed  on  ice.  Quantities  of  2  c.c.  each  of 
the  blood  are  then  placed  in  a  series  of  seven  small  (nonsol)  test  tubes 
and  allowed  to  stand  for  five  to  six  minutes  in  order  to  permit  a  narrow 


42  PHYSICOCHEMICAL    BASIS   OF    PHYSIOLOGICAL    PROCESSES 

layer  of  plasma  to  separate  on  the  surface  (this  prevents  taking  of  the 

blood  during  the  subsequent  addition  of  acid  or  alkali).  The  blood  in 
the  first  tube  is  used  for  the  determination  of  the  normal  H-ion.  In 
eaeh  of  the  next  three  tubes  are  added  respectively  0.1,  0.2  and  0.3  c.c. 
N  50  HO,  and  to  the  last  three,  similar  quantities  of  X  50  Na<  >H.  After 
inverting  the  tubes  so  as  to  mix  the  contents,  the  blood  in  eaeh  is  trans- 
ferred to  celloidin  sacs  and  the  CH  determined  according  to  the  method 
described  elsewhere  (page  32). 

The  tubes  are  noted  in  which  a  change  in  tint  from  that  of  the  normal 
blood  is  evident,  and  the  results  are  expressed  as  the  c.c.  of  N/50  IK  11 
or  NaOH  which  must  be  added  to  blood  to  change  its  C„.  Thus,  the 
alkali  buffer  is  the  c.c.  of  N/50  NaOH  which  can  be  added  to  2  c.c.  of 
blood  without  change  of  CH  of  the  dialysate,  and  the  acid  hit  fur  the  c.c. 
of  N/50  HC1. 

The  method  suffers  from  the  following  drawbacks: 

1.  Very  small  quantities  of  acid  and  alkali  are  employed. 

2.  .It  is  often  difficult  to  tell  just  exactly  when  a  slight  difference  in 
tint  has  been  produced. 

3.  Even  with  the  precautions  described  above,  it  is  impossible  to  be 
sure  that  the  amount  of  C02  in  the  different  samples  of  blood  is  the  same, 
which  means,  of  course,  that  some  bloods  will,  on  this  account  alone,  be 
able  to  bind  more  alkali  than  others. 

The  Method  of  Van  Slyke. — A  method  based  on  somewhat  the  same 
principle,  but  which  is  more  accurate  because  it  meets  the  above  objec- 
tion, is  that  sucrsested  by  Van  Slyke.  Stillman  and  Cullen.14  Plasma  is 
freed  of  C02  by  placing  it  in  a  vacuum,  and  is  then  mixed  with  an  equal 
volume  of  N/50  HC1  (or  XaOH)  and  the  CH  determined  by  the  electric 
method  (see  page  29).  In  the  case  of  normal  blood,  after  such  an  addi- 
tion of  acid,  a  practically  normal  CH  will  be  found,  whereas  in  the  blood 
of  cases  of  acidosis  it  will  be  very  distinctly  increased  (i.e.,  P„  lower). 

2.  CO.-combining  Power 

The  above  objections  to  the  titration  of  blood  plasma  or  dialysate 
with  standard  solutions  of  acids  are  removed  if  we  measure  the  com- 
bining power  of  the  blood  alkali  towards  carbonic  acid  itself  at  normal 
blood  reaction.  This  may  be  done  either  in  blood  immediately  after  its 
removal  from  the  animal  or  in  blood  that  has  been  first  of  all  saturated 
outside  the  body  Avith  carbonic  acid  at  a  partial  pressure  equal  to  that 
existing  in  the  body.  Since  for  practical  reasons  venous  blood  must  be 
used — in  the  clinic  at  least — the  former  of  these  methods  suffers  from 
the  fault  that  varying  amounts  of  carbonic  acid  will  be  added  to  the 
blood'  during  its  passage   through   the   tissues,   and  the   error  thereby 


ACIDOSIS 


43 


incurred  will  become  greatly  aggravated  if  venous  stasis  has  been  pro 
duced  in  drawing  the  specimen  for  analysis.  But  the  chief  reason  why 
this  method  has  not  been  extensively  employed,  as  pointed  <>ui  by  Van 
Slyke,  is  the  technical  difficulty  of  making  the  necessary  analysis. 

It  is  most  satisfactory  to  colled  xenons  blood  after  a  period  (one  hour 
at  least")  of  muscular  rest  (so  that  there  is  no  excess  of  C02)  and  without 
venous  stasis,  and  to  centrifuge  without  permitting  any  considerable  loss 
of  carbonic  acid.  The  latter  precaution  is  necessary  because  there  is  a 
migration  of  acid  radicles,  e.  g.,  HC1,  from  plasma  into  corpuscles  when 
the  C02  of  the  former  is  increased,  and  in  the  reverse  direction  when  the 
C02  is  decreased.  If  the  C02  in  the  blood  Avere  not  the  same  during  cen- 
trifuging  as  it  is  in  the  body,  the  separate  plasma  "would  not  contain  the 
same  amount  of  alkali — i.  e.,  its  reserve  alkalinity  would  be  altered. 
Although  theoretically,  therefore,  centrifuging  should  be  performed  in 


Fig.  10. — Diagram  of  apparatus  for  saturating  blood  or  plasma  with  expired  air.  The  glass 
beads  in  the  bottle  condense  excess  of  moisture.  The  separating  funnel,  as  soon  as  it  has  been 
filled  with  expired  air,  should  be  closed  by  a  stopper  and  the  stopcock  turned  off.  It  is  then 
rotated    so    that    the    blood    forms    a    film    on    its    walls. 

an  atmosphere  containing  the  same  partial  pressure  of  C02  as  exists  in 
the  body  (i.  e.,  the  alveolar  air)  (see  page  344),  this  has  been  found  im- 
practicable for  general  use,  and  is  unnecessary  if  loss  of  C02  from  the 
specimen  of  blood  is  prevented  by  allowing  it  to  flow  into  the  syringe 
very  slowly  (without  any  suction).  It  is  mixed  in  the  syringe  with 
powdered  (neutral)  potassium  oxalate  (enough  to  make  a  1  per  cent 
solution  with  the  blood),  and  immediately  delivered  into  a  centrifuge 
tube  under  paraffin  oil,  which  by  floating  on  its  surface  serves  to  diminish 
free  diffusion  of  C02  to  the  outside  air  (even  though  such  oils  dissolve 
more  C02  than  water).  To  mix  the  blood  with  the  oxalate,  the  syringe 
should  be  moved  backward  and  forward  several  times,  but  it  must  not  b<> 
shaken. 

After  centrifuging,  about  3  c.c.  of  plasma  are  removed  and  saturated 
with  CO,  at  the  same  tension  as  in  alveolar  air  (i.  e.,  5.5  per  cent).    This 


44 


PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 


is  done  by  placing  the  plasma  in  a  separating  funnel  of  300  c.c.  capacity, 
laying  the  funnel  on  its  side  and  displacing  the  air  in  it  by  alveolar  air 
secured  by  quickly  making  as  deep  an  inspiration  as  possible  through 
the  tube  and  bottle  containing  glass  beads  (Fig.  10).  The  glass  beads 
remove  excess  of  water  vapor  from  the  air.  The  funnel  must  be  restop- 
pered  before  the  end  of  the  expiration,  so  that  no  outside  air  enters.  It 
is  then  rotated,  for  about  two  minutes,  in  such  a  way  that  the  plasma 
forms  a  film  on  its  walls.  If  it  is  necessary  to  postpone  the  saturating 
of  the  plasma,  this  should  be  pipetted  off  from  the  corpuscles  and  pre- 
served in  hard  glass  test  tubes  coated  with  paraffin.    From  ordinary  glass 


Fig.   11. — Van   Slyke's  apparatus  for   measuring  the   CO^-combining  power   of  blood   in   blood   plasma. 
For    description,    see    context. 


enough  alkali  is  soon  dissolved  out  to  vitiate  the  results.  After  saturation 
of  the  plasma  with  C02,  the  funnel  is  placed  in  the  upright  position  and 
the  plasma  allowed  to  collect  in  the  narrow  portion,  after  which  1  c.c. 
is  removed  with  an  accurate  pipette  and  analyzed  for  C02. 

The  analysis  may  be  done  by  using  either  the  Van  Slyke  or  the  Hal- 
dane-Barcroft  apparatus.    The  Van  Slyke  method  is  as  follows: 

The  apparatus  is  filled  to  the  top  of  the  graduated  tube  with  mercury 
(Fig.  11)  by  raising  the  mercury  reservoir  F,  care  being  taken  that 
D  and  E  are  also  filled.    One  c.c.  of  the  C02-saturated  plasma  is  then  de- 


ACIDOSIS  45 

livered  into  A  (which  has  been  rinsed  out  with  C02-free  ammonia  water), 
and  the  stopcock  /  turned  so  that  by  cautiously  lowering  the  level  of  the 
reservoir  F,  the  plasma  runs  into  B  (but  no  trace  of  air).  The  same 
procedure  is  repeated  with  1  c.c.  water,  so  as  to  wash  in  all  of  the  plasma, 
and  finally  0.5  c.c  of  5  per  cent  II2S04  is  sucked  in,  after  which  stopcock  / 
is  turned  off.  The  reservoir  F  is  then  lowered  sufficiently  to  allow  all 
of  the  mercury,  but  none  of  the  blood,  to  run  Out  of  B  and  C.  A  vacuum 
is  thus  produced  in  B  and  C. 

As  the  level  of  the  mercury  falls  in  B  and  C,  the  plasma  effervesces  vio- 
lently,* because  it  is  exposed  to  a  vacuum.  To  be  certain  that  all  traces  of 
C02  have  been  dislodged  from  the  solution,  the  apparatus  is  inverted 
several  times.  To  ascertain  how  much  C02  has  been  liberated,  stopcock  // 
is  now  turned  so  as  to  bring  C  and  E  into  communication,  and  by  cautiously 
lowering  the  reservoir  the  fluid  in  C  is  allowed  to  run  into  the  bulb  E. 
Stopcock  11  is  thereafter  turned  so  as  to  connect  C  and  D,  and  the  reser- 
voir raised  so  that  the  mercury  runs  into  C  as  far  as  the  C02  that  has  col- 
lected in  the  burette  will  permit  it  to  go.  After  bringing  the  level  of  the 
mercury  in  F  to  correspond  to  that  in  the  burette,  the  graduation  at  which 
this  stands  is  read.  It  gives  the  c.c.  of  C02  liberated  from  the  plasma. 
Under  the  above  conditions  normal  plasma  binds  about  75  per  cent  of 
its  volume  of  C02 ;  therefore,  since  the  total  capacity  of  the  pipette  is  50 
c.c,  the  mercury  should  stand  at  0.375  c.c.  on  the  burette.  For  accurate 
measurement  it  is  necessary  to  allow  for  the  CO,  that  remains  dissolved 
in  the  water,  etc.,  as  well  as  for  barometric  pressure  and  temperature. 
This  is  best  done  by  the  use  of  a  table  based  on  the  known  solubility  of 
C02  under  the  various  conditions  obtaining,  which  is  given  in  Van 
Slyke's  paper.12 

The  Haldane-Barcroft  apparatus  that  is  most  suitable  for  the  above 
analysis  is  shown  in  Fig.  136,  page  382.  t  One  c.c.  of  C02-free  ammonia 
water  is  placed  in  the  bottle  and  the  1  c.c.  of  plasma  delivered  beneath  it. 

*This   may  be  prevented   by  adding  a  small   drop   of  caprylic   alcohol. 

fThis  form  of  Haldane-Barcroft  apparatus  is  not  quite  the  same  as  the  differential  manometer 
that  is  used  for  measurement  of  the  Oo-combining  power  of  hemoglobin  (page  382).  In  the  form 
used  for  the  present  purpose,  a  side  tube  at  the  bend  of  the  U-tube  is  connected  with  a  small  rub- 
ber bag,  which  dan  be  compressed  by  a  screw.  When  the  gas  is  evolved  in  the  bottle,  it  presses 
down  the  fluid  in  the  proximal  limb  of  the  manometer  correspondingly  and  raises  that  in  the  distal 
limb.  Since  the  calculation  of  the  amount  of  gas  evolved  depends  on  finding  the  pressure  produced 
without  any  change  in  volume,  it  is  necessary  after  the  gas  has  been  evolved  to  compress  the  rubber 
bag  until  the  meniscus  of  fluid  in  the  proximal  limb  of  the  manometer  is  brought  back  to  its  original 
level.  The  height  at  which  the  fluid  stands  in  the  distal  limb  then  obviously  corresponds  to  the 
pressure  created  by  the  evolved  gas. 

The  equation  for  determining  the  amount  of  gas  evolved  depends  on  the  gas  law,  which  states 
that  the  pressure  of  a  gas  is  inversely  proportional  to  its  volume  (page  336).  Suppose  that  the 
volume  of  gas  evolved  was  equal  to  the  volume  of  the  bottle,  then,  since  the  volume  has  been 
kept  constant,  the  pressure  would  be  doubled — that  is,  the  fluid  in  the  distal  limb  would  equal  that 
of  1  atmosphere,  or  10,400  mm.  of  water  or  10,000  of  clove  oil,  which  is  the  fluid  actually  used  to 
fill  the  manometer.  Any  other  observed  pressure  would  therefore  correspond  to  the  volume  of 
evolved   gas  according  to   the  equation, 

vol.  of  bottle   (and  tubing  to  meniscus) 

10,000  (when  clove  oil  is  used) 

In  using  the  apparatus  in  the  above  manner,  only  one  of  the  bottles  is  employed,  and  the  tartaric 
acid  is  added  from  a  pocket  in  the  stopper  by  a  simple  manipulation. 


4G  PHYSlCOCHIvMICAL   BASIS   OF   PHYSIOLOGICAL    I'KOCI.SSES 

The  bottle  is  then  connected  with  the  manometer  with  the  precautions 
described  elsewhere  in  this  volume.  When  temperature  conditions  have 
been  allowed  for,  saturated  tartaric  acid  is  mixed  with  the  plasma  solu- 
tion and  the  gas  evolved  measured  by  the  displacement  of  the  fluid  in  the 
manometer.  The  apparatus  may  also  be  used  with  blood  in  place  of 
plasma.  In  this  case,  however,  it  is  necessary  that  the  oxygen  be  removed 
before  adding  the  tartaric  acid.  This  precaution  is  necessary,  since  acid 
can  dislodge  some  of  the  02  from  hemoglobin.  The  blood  is  therefore  first 
of  all  laked  with  ammonia  containing  some  saponin,  then  shaken  with 
0.25  c.c.  saturated  potassium  ferricyanide  solution,  and  finally  with  the 
saturated  acid  solution.  If  blood  is  used,  the  estimations  must  be  made 
on  strictly  fresh  blood,  since  on  standing  the  CO,-combining  power 
greatly  deteriorates. 

3.  Indirect  Methods 

There  are  several  other  methods  by  which  the  alkaline  reserve  may  be 
measured.    These  include: 

1.  Determination  of  the  Tension  of  C02  in  Alveolar  Air  (page  344). — 
Since  this  method  is  employed  more  particularly  in  investigating  the 
hormone  control  of  the  respiratory  center,  we  shall  defer  a  description 
of  it  until  later.  The  alveolar  CO,  tension  corresponds  to  the  CO,  ten- 
sion in  arterial  blood  and  this  is  proportional  to  the  alkaline  reserve  as 
determined  by  Van  Slyke's  method  as  is  proved  by  the  fact  that  the  ratio, 

plasma  CO,  .        ..«..,  .      , 

i ; — -prpr — - : — ,  is  satistaetori ly  constant. 

alveolar  CO,  tension 

2.  The  Measurement  of  the  Acid  Excretion  by  the  Kidney. — As  might 
be  expected,  the  acid-base  equilibrium  of  the  body  may  also  be  gauged  by 
measurement  of  the  acid  excretion  of  the  urine,  in  which  the  acids  are 
contained  partly  in  combination  with  ammonia  or  a  fixed  base,  and  partly 
in  a  free  state.  We  shall  first  of  all  consider  the  methods  of  acid 
excretion  and  then  examine  the  evidence  showing  that  the  total  acid 
excretion  is  proportional  to  the  alkaline  reserve  as  measured  by  the 
above  described  methods. 

Excretion  of  Acid  in  Combination  with  Ammonia. — The  production 
of  ammonia  is  essentially  an  endogenous  process,  and  when  excessive 
quantities  of  acid  make  their  appearance  in  the  organism,  the  fixed  alkali 
may  not  be  sufficient  to  neutralize  it  all,  so  that  ammonia,  derived  from 
the  breakdown  of  amino  acids  (page  616),  instead  of  being  converted 
into  urea  is  employed  to  neutralize  the  excess  of  acid.  Most  workers 
have  in  this  way  explained  the  very  large  ammonia  excretion  that  has 
long  been  known  to  occur  in  such  conditions  as  diabetic  acidosis.  Some 
recent  workers   are,   however,   inclined   to   question   the   significance   of 


ACIDOSIS  47 

ammonia  in  this  connection,  believing  thai  the  increased  ammonia  ex- 
cretion is,  like  the  acetone  bodies  themselves,  a  product  of  perverted 
metabolism.  Be  ibis  as  it  may,  it  is  no  doubt  true  that  ammonia  is  used 
for  neutralizing  acid  in  disease,  although  it  may  not  be  an  important 
factor  in  the  maintenance  of  neutrality  under  normal  conditions.  It  is 
a  factor  of  safety,  in  that  it  helps  to  care  for  an  increase  in  acid  when 
the  normal  mechanism  of  the  body  is  overtaxed. 

Excretion  of  Phosphates. — The  more  permanent  control  of  neutrality 
depends  on  the  excretion  of  phosphates  by  the  kidney.  The  principle 
governing  this  process  is  exactly  the  same  as  that  already  discussed  in 
connection  with  carbonic  acid.  In  the  one  case  it  is  the  volatile  acid 
CO.,,  and  in  the  other,  the  fixed  phosphoric  acid  that  is  concerned  in  the 
reaction.  The  ratio  between  the  acid  salts  of  phosphoric  acid,  MII2PO.,, 
and  the  alkaline  salts,  MJIP04,  in  blood  is  approximately  1  to  5,  but  in 
the  urine  this  ratio  varies  according-  to  the  amount  of  II  ion  that  must 
be  eliminated  from  the  blood.  In  other  words,  a  definite  amount  of  phos- 
phoric acid  is  enabled  to  carry  variable  amounts  of  II  ion  out  of  the  body 
by  causing  the  amount  of  alkali  excreted  in  combination  with  it  to  be- 
come altered.  For  example,  in  the  form  of  MH2P04  a  given  amount  of 
P04  obviously  carries  out  more  H  ion  than  when  it  is  excreted  as 
M2HP04.  The  adjustment  between  these  two  salts  is  a  function  of  the 
kidney.  We  may  accordingly  measure  the  amount  of  alkali  retained  by 
the  organism  by  finding  how  much  standardized  alkali  must  be  added 
to  a  given  quantity  of  urine  until  the  reaction  of  the  blood  is  obtained. 
Since  the  latter  value  is  constant,  the  titration  can  be  done  simply  by 
titrating  the  urine  with  an  indicator  such  as  sulphonephenolphthalein, 
which  changes  tint  at  about  PH  of  blood. 

A  more  serviceable  indicator  to  use,  however,  is  phenolphthalein,  be- 
cause its  end  point  is  such  that  when  human  urine  just  reacts  neutral 
to  it — that  is,  when  the  titrable  acid  approaches  zero — the  C02-absorb- 
ing  power  of  the  plasma  is  at  its  maximum  of  80  vols,  per  cent  and  the 
ammonia  excretion  by  the  urine  is  zero  (Van  Slyke).  It  is  advantageous, 
therefore,  to  use  this  indicator,  because  it  happens  to  have  its  turning 
point  situated  for  a  reaction  which  is  well  to  the  alkaline  side  of  neu- 
trality, and  which  is  reached  in  urine  when  the  blood  is  at  its  maximal 
acid-combining  power  and  no  ammonia  is  being  used  for  neutralization 
purposes.  As  the  C02-combining  power  of  the  blood  decreases,  there 
should,  therefore,  be  a  proportionate  increase  in  ammonia  and  in  the 
titrable  acidity  of  the  urine. 

Although  a  general  parallelism  exists  between  these  values  in  cases  of 
diabetes,  etc.,  there  is  no  strict  proportionality.  The  expedient  has 
therefore  been  tried  of  comparing  the  alkaline  reserve  of  the  blood  with 


48  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

the  excretion  rate  of  acid  as  determined  by  an  application  of  Ambard's 
equation  for  chlorides  and  urea,  and  with  curiously  satisfactory  results 
(Fitz  and  Van  Slyke).     This  equation  is: 


Blood  concentration  =  constant  x  y™-  yC;  where  D  is  the   excretion 

rate,  W  the  body  weight,  and  C  the  concentration  of  excretory  prod- 
uct in  the  urine.  For  the  present  purpose  D  is  therefore  the  number  of 
c.c.  of  N/10  alkali  (or  acid)  required  to  bring  the  urine  to  the  neutral 
point  of  phenolphthalein  plus  the  NH3  expressed  as  c.c.  of  an  N/10  solution, 
for  the  twenty-four  hours,  and  C  is  c.c.  of  N/10  alkali  and  of  N/10  NH3 
per  liter  of  urine.  If  we  assume  that  the  acid  accumulation  in  the  blood 
is  proportional  to  the  fall  of  the  plasma  C02  figure  below  the  maximal 
figure  of  80,  the  above  equation  becomes: 


Retained   acid  =  80  -  plasma  CO,  =  constant  x  ^  tj^  VC. 

For  practical  purposes  it  is  best  to  make  the  necessary  analysis  on  a 
sample  of  urine  collected  over  a  period  of  one  to  four  hours,  and  to  col- 
lect the  blood  for  determination  of  its  reserve  alkalinity  in  the  middle 
of  this  period.  The  twenty-four-hour  rate  of  excretion  is  then  computed 
(D)  from  the  analysis. 

The  value  calculated  by  the  above  equation  has  been  found  to  agree 
with  that  of  the  C02-combining  power  of  the  plasma  to  within  10  vol- 
umes per  cent,  except  when  bicarbonate  is  being  taken  by  the  person, 
when  the  blood  bicarbonate  is  much  higher  than  indicated  by  the  urine. 

3.  Determination  of  Alkali  Retention. — Another  valuable  criterion  of 
the  alkaline  reserve  is  the  amount  of  alkali  required  to  change  the  re- 
action of  the  urine.  In  health  the  CH  of  the  urine  varies  from 
0.000,016  N  (PH  =  4.8)  to  about  0.000,000,035  N  (PH  =  7.46)  with  a  mean 
of  about  0.000,001  N  (PH  =  6).  These  extremes  are  rarely  overstepped 
in  disease,  but  frequently  the  average  is  considerably  different.  In  car- 
dio-renal  disease,  for  example,  the  mean  acidity  may  be  approximately 
0.000,005  N  (PH  =  5.3),  or  five  times  the  normal  value.  A  certain  de- 
gree of  acidosis  is  therefore  common  enough  in  this  condition- — a  fact 
which  has  indicated  the  advisability  of  administering  sodium  bicarbon- 
ate. It  has  been  found  that  5  grams  or  less  of  soda,  given  by  mouth  to 
a  normal  person,  causes  a  distinct  diminution  in  the  CH  of  the  urine, 
whereas  in  pathologic  cases  it  may  be  necessary  to  give  more  than  100 
grams  before  a  similar  effect  is  observed  (L.  J.  Henderson  and  Palmer15 
and  Sellards16). 

For  this  very  large  holding  back  of  alkali,  the  organism  and  not  the 
kidney  is  responsible.  This  is  indicated  by  the  fact  that,  when  the 
administration  of  alkali  is  discontinued,  the  acidity  of  the  urine  soon 


ACIDOSIS  49 

regains  its  old  level,  although  now  if  a  smaller  dose  of  alkali  is  given, 
the  CH  of  the  urine  will  immediately  be  lowered.  These  facts  indicate 
that  for  the  moderate  degrees  of  acidosis  common  in  chronic  disease,  the 
properly  controlled  administration  of  soda  is  very  probably  a  most  advan- 
tageous treatment. 


CHAPTER  VII 
COLLOIDS 

Substances  which  can  be  obtained  in  the  crystalline  state  and  which, 
when  in  solution,  are  capable  of  readily  diffusing  through  membranes, 
are  designated  as  crystalloids,  and  are  to  be  distinguished  from  another, 
larger  group  of  substances  not  having  these  characteristics  or  having 
them  only  in  very  minor  degree — the  colloids.  In  every  field  of  chem- 
istry the  properties  of  colloids  have  been  studied  extensively  during 
recent  years,  but  in  no  field  more  than  in  that  which  covers  the  chem- 
istry of  biological  fluids  and  tissues,  into  whose  composition  colloids 
enter  much  more  extensively  than  crystalloids.  The  subject  of  colloidal 
chemistry  has  indeed  become  so  extensive  that  an  attempt  to  do  more 
than  indicate  some  of  the  most  important  characteristics  of  colloids 
would  take  us  far  beyond  the  limitations  of  this  book.  The  far-reaching 
applications  of  the  subject  in  physiology  and  medicine  are  only  begin- 
ning to  be  realized. 

The  term  "colloid,"  or  "colloidal,"  does  not  refer  to  a  class  of  chemical 
substances,  but  rather  to  a  state  of  matter  which  is  quite  independent 
of  the  chemical  composition  of  the  substance.  We  are  familiar  with 
more  colloids  in  the  organic  than  in  the  inorganic  world,  yet  they  are 
plentiful  in  both,  and  the  same  substance  may  at  one  time  be  colloidal 
and  at  another  noncolloidal.  Indeed,  under  appropriate  conditions  prob- 
ably all  substances  may  assume  the  colloidal  state — not  solids  and  liq- 
uids alone,  but  gases  as  well.  It  is  mainly  with  liquids,  however,  that 
Ave  are  concerned  in  biochemistry. 

CHARACTERISTIC  PROPERTIES 

The  distinction  between  molecular*  and  colloidal  solutions  is  a  rela- 
tive one.  Suppose,  for  example,  that  we  take  a  piece  of  gold  in  water 
and  divide  it  up  into  smaller  and  smaller  parts.  At  a  certain  stage,  the 
particles  will  be  so  fine  that  they  will  remain  in  suspension  and  be  in- 
visible by  ordinary  means.  They  are  then  said  to  be  in  the  colloidal 
state.  If  we  divide  them  further  until  they  become  molecules  of  gold, 
a  molecular  solution  will  be  obtained.     In  the  colloidal  state,  there  are 


*Molecular    solutions    include    those    of    nonclectrolytes,    such    as    sugar,    and    electrolytes,    such   as 
inorganic  salts. 

50 


COLLOIDS  51 

two  distinct  phases  in  the  solution,  one  solid  and  the  oilier  Liquid,  and 
between  the  two,  because  of  the  greal  subdivision  of  the  original  par- 
ticle, is  an  enormous  surface  of  contact.  The  solution  is  heterogeneous, 
and  at  the  interface  between  the  two  "phases"  the  physical  forces  which 
depend  on  surface — e.  g.,  surface  tension  (see  page  64) — are  enormously 
developed,  and  are  responsible  for  the  peculiar  properties  of  colloidal 
solutions  as  compared  with  those  of  molecular  solutions,  which  may, 
therefore,  be  styled  homogeneous.  The  solutions  of  crystalline  substances 
which  we  have  hitherto  been  concerned  with,  arc  homogeneous. 

Between  these  two  groups  of  solutions  is  an  intermediate  one — namely, 
suspensions  (as  suspensions  of  quartz  or  carbon,  or  oil  emulsions).  Be- 
sides being  turbid  in  transmitted  light,  the  solutions  may  be  seen  by 
means  of  the  ultramieroseope  to  contain  particles.  These  can  be  sepa- 
rated by  filtration  from  the  fluid  they  are  suspended  in,  except  in  the 
case  of  many  emulsions  in  wrhich  the  particles  can  squeeze  their  way 
through  the  filter  pores  by  changing  their  shape.  On  standing  or  being 
centrifuged  suspensions  may  also  separate  into  their  constituents,  al- 
though this  can  be  greatly  hindered  by  the  addition  of  a  suspending 
substance  such  as  gelatin  or  certain  bodies  having  a  so-called  protec- 
tive action  (as  peptone,  proteose,  etc.). 

True  Colloidal  Solutions 

1.  The  Solution  Is  More  or  Less  Turbid. — Frequently  this  can  be  recog- 
nized by  holding  the  solution  in  a  thin-walled  glass  vessel  against  a 
dark  background,  but  the  turbidity  may  be  so  slight  that  it  requires 
for  its  detection  the  use  of  the  Tyndall  phenomenon.  This  is  familiar 
to  all  in  the  effect  of  a  beam  of  sunlight  let  in  through  a  small  aperture 
into  an  otherwise  darkened  room.  In  the  course  of  the  beam  suspended 
dust  particles,  which  are  invisible  in  an  equally  illuminated  room,  be- 
come visible,  and  thus  render  very  distinct  the  pathway  of  the  beam. 
If  a  colloidal  solution  contained  in  a  glass  vessel,  preferably  with  paral- 
lel sides,  is  held  in  the  course  of  such  a  beam,  the  Tyndall  phenomenon 
will  be  seen  in  the  liquid,  which  is  not  the  case  with  molecular  solutions. 
Focused  artificial  light  may  be  employed  for  intensifying  the  effect. 
The  light  that  is  sent  out  at  right  angles  to  the  beam  is  plane-polarized, 
which  means  that  the  particles  reflecting  the  light  must  be  smaller  than 
the  mean  wave  length  of  the  light  forming  the  beam.  It  should  be  under- 
stood that  the  individual  particles  themselves  may  not  be  rendered 
visible  to  the  naked  eye  by  the  beam,  although  in  such  cases  they  can 
often  be  seen  by  using  intense  illumination  and  a  dark-field  (ultramiero- 
seope) combined  with  suitable  magnification  (Fig.  12). 

2.  Colloids  Do  Not  Readily  Diffuse. — To  demonstrate  this,  test  tubes 


52 


PHYSICOCHEMICAL   BASIS    OF   PHYSIOLOGICAL   PROCESSES 


are  half  filled  with  a  5  per  cent  solution  of  pure  gelatin  or  a  1  per  cent 
solution  of  pure  agar,  and,  after  the  jelly  is  set,  the  solution  under 
examination  is  poured  on  the  surface;  or,  when  it  is  of  high  spe- 
cific gravity,  the  tube  of  gelatin,  etc.,  is  placed  mouth  downwards  in 
the  solution.  In  the  case  of  colloidal  solutions  very  little  if  any  diffu- 
sion into  the  gelatin  or  agar  will  occur,  even  after  several  days;  whereas 
true  molecular  solutions  will  diffuse  for  a  considerable  distance.  When 
colored  solutions  are  used,  the  diffusion  can  readily  be  recognized  by 
visual  inspection  (see  Fig.  13),  but  when  they  are  colorless,  the  presence 
or  absence  of  diffusion  must  be  determined  by  removing  the  column 
of  gelatin  or  agar  and  dividing  it  into  slices  of  equal  size,  which  are 
then  examined  chemically  for  the  substance  in  question. 

A  further  test  is  afforded  by  the  failure  of  colloids  to  diffuse  through 
membranes  (dialysis).  This  was  the  method  originally  used  by  Thomas 
Graham  to  distinguish  between  molecular  and  colloidal  solutions.  The 
solution  under  examination  is  placed  in  a  dialyzer,  which  is  then  im- 
mersed in  a  wide  vessel  containing  the  pure  solvent.     The  older  forms 


Fig.  12. — Ultramicroscope  (slit  type)  for  the  examination  of  colloidal  solutions.  The  arrange- 
ment of  diaphragms,  etc.,  in  this  form  removes  the  absorptive  effects  of  the  surfaces  of  the  glass 
vessel    or   slide   vised   to   contain   the   colloidal    solutions. 


of  dialyzer  consisted  in  general  of  a  bell-shaped  glass  vessel  closed  be- 
low with  parchment  paper,  but  more  recently  so-called  diffusion  sacs 
have  been  adopted.  These  consist  of  pig  or  fish  bladders  or  of  col- 
lodion sacs.  The  latter  are  made  by  placing  some  collodion  dissolved 
in  ether  in  a  test  tube,  which  is  then  tilted  so  that  the  collodion  runs 
out  except  for  a  thin  layer  which  remains  adherent  to  the  walls.  When 
the  collodion  has  set,  the  sac  can  be  removed  after  loosening  it  by  allow- 
ing a  little  water  to  flow  between  the  sac  and  the  walls  of  the  test  tube. 
The  sac  containing  the  colloidal  solution  is  then  suspended  in  water 
or  some  of  the  solvent  used  in  preparing  the  colloidal  solution,  care 
being  taken  that  the  menisci  of  the  fluids  inside  and  outside  of  the  sac 
stand  at  the  same  level.  Sometimes,  especially  when  collodion  sacs  are 
used,  some  colloid  may  at  first  diffuse  through,  but  if  the  outer  fluid 
(the  dialysate)  is  renewed  and  the  dialysis  allowed  to  proceed,  this 
ceases. 


COLLOIDS 


53 


When  a  fluid  solution  exhibits  both  of  the  above  properties  (i.e.,  the 
Tyndall  phenomenon  and  indiffusibility ) ,  there  can  be  no  douhl  as  to  its 
being  in  a  true  colloidal  state,  but  there  are  substances,  such  as  eongo 
red  or  protein  solutions  of  certain  strengths,  which  may  exhibit  a  very 
slight  dilTusibility  in  a  dialyzer  but  not  show  the  Tyndall  phenomenon. 
Substances  of  this  group  constitute  transitional  types  between  molecular 
and  colloidal  solutions,  and  to  determine  their  true  nature  it  is  neces- 


Fig.    13. — To    show    diffusion    into    gelatin    of    a    crystalloid    stain    in    b    and    the    nondiffusion    of    a 
colloid    stain    in    a.       (From    W.     Ostwald.) 

sary  to  employ  refined  methods  such  as  those  of  ultramicroscopy,  ultra- 
filtration, etc.,  which  can  not  be  described  here. 

3.  The  Size  of  Colloidal  Particles.— It  will  be  apparent  that  the  essential 
property  upon  which  the  above-mentioned  phenomena  depend  is  the  size 
of  the  particle.  Particles  which  can  still  be  seen  under  the  microscope 
are  called  microns.  They  have  been  computed  to  have  a  dimension  of 
0.1  fx  (0.001  mm.)  or  more,  and  they  form  suspensions.  Particles  which 
are  invisible  microscopically  under  the  ordinary  conditions-  of  illumina- 


54 


PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 


tion,  but  are  still  visible  when  the  ultramicroseopic  illumination  is 
used,  are  called  submicrons.  They  have  a  dimension  between  0.1  /*  and 
1  /x/x  (0.000,001  mm.),*  and  they  constitute  the  colloids.  Particles  smaller 
than  1  fi/x  are  called  amicrons,  this  term  being  used  to  include  the  mol- 
ecules and  ions  present  in  molecular  solutions.  (The  amicron  of  hydro- 
gen is,  for  example,  computed  to  be  0.067  to  0.159  /x/x,  and  that  of  water 
vapor,  0.113  fi/x.)  This  classification  of  dissolved  substances  according 
to  the  size  of  the  particles  and  molecules  shows  the  relationship  of  one 


y  V.t-.c 


Fig.    14. — Diagram    from    \V.    Ostwald    showing    the    relative    size    of    various    particles    and    colloidal 
dispersoids    compared    with    a    red    blood    corpuscle    and    an    anthrax    bacillus. 

class  of  substances  to  others.  An  idea  of  the  relative  sizes  of  colloidal 
particles  and  molecules  in  comparison  with  such  familiar  objects  as  a 
blood  corpuscle  and  an  anthrax  bacillus  is  given  in  Fig.  14.  The  fluid 
in  which  the  "particle"  is  suspended  is  called  the  dispersion  medium,  or 
external  phase,  and  the  particle  itself  the  dispersoid,  or  internal  phase. 
It  is  the  enormous  development  of  surface  which  determines  the  dif- 


*M.  —  0.001    mm.,   and   fifi  =  0.000,001    mr 


COLLOIDS  55 

ference  in  the  properties  of  a  colloidal  solution  from  those  of  a  suspen- 
sion of  the  same  substance.  Thus,  the  difference  between  a  colloidal 
solution  of  platinum  (prepared  by  allowing  an  electric  ace  to  form  be 
tween  platinum  electrodes  in  water)  and  pieces  of  platinum  in  water 
depends  on  the  fact  that  the  surface  of  the  platinum  in  the  former  case 
has  been  increased  many  million  times.  When  the  subdivision  becomes 
still  greater  and  the  particles  gain  the  size  of  molecules,  the  phenomena 
due  to  surface  development  become  suppressed  and  those  due  to  con- 
centration in  uiut  volume  become  accentuated.  The  properties  depend- 
ent on  osmotic  pressure,  diffusibility,  etc.,  are  exhibited  by  all  dispersoids, 
whether  ions,  molecules  or  particles,  but  some  of  these  properties  are 
much  more  pronounced  when  the  dispersoids  are  of  large  dimensions, 
and  others  when  they  are  small.  In  other  words,  the  phenomena  due  to 
surface,  such  as  those  of  surface  tension  (see  page  64),  become  apparent 
only  when  the  dispersoids  have  the  properties  of  matter  in  mass;  when 
the  dispersoids  become  molecular  in  size,  they  manifest  the  properties 
characteristic  of  true  solutions. 

4.  Electric  Properties  of  Colloids. — Most  colloids  carry  a  charge,  which 
may  be  either  positive  or  negative  toward  the  dispersion  medium.  Both 
crystalloids  and  colloids  therefore  carry  electric  charges;  in  the  former 
ease,  however,  the  charge  does  not  reveal  itself  until  the  molecules  in 
solution  have  become  dissociated,  when  each  ion  carries  a  charge  of 
opposite  sign  (see  page  16),  whereas  in  the  case  of  colloids,  each  col- 
loid particle  usually  carries  a  charge  which  is  always  of  one  sign,  either 
positive  or  negative.  Colloids  may  therefore  be  grouped  into  positive 
and  negative,  according  to  the  charges  which  they  carry,  and  there  is 
a  third  group  in  which  the  charge  may  be  either  positive  or  negative  ac- 
cording to  the  nature  of  the  dispersion  medium. 

A  colloid  not  carrying  a  charge  to  begin  with  can  be  caused  to  assume 
one  by  the  action  of  electrolytes,  for  the  electrical  properties  of  colloids, 
as  well  as  those  of  inert  powders  suspended  in  water,  are  readily  in- 
fluenced by  the  charges  present  in  the  ions  of  the  dispersion  medium. 
The  H-  and  OIF  ions  are  especially  liable  to  exert  this  influence.  The 
particles  of  inert  powders  in  suspensions  (kaolin,  sulphur,  etc.)  carry 
a  positive  charge  when  the  water  in  which  they  are  suspended  is,  acidi- 
fied, and  a  negative  charge  when  it  is  made  alkaline.  In  general,  it  may 
be  said  that  suspensions  of  most  powders  and  of  insoluble  organic  acids 
in  water  (e.  g.,  charcoal,  cellulose,  kaolin,  caseinogen,  mastic,  free  acid 
of  congo  red,  etc.)  are  electro-negative.  Of  true  colloids  ferric  hydrox- 
ide (ferruin  dialysatum)  and  serum  globulin  are  positive  in  acid  solu- 
tions; arsenious  sulphide  and  serum  globulin  are  negative  in  alkaline 
solution,  and  serum  globulin  in  neutral  solutions  has  no  charge. 


56  PHYSICOCHEMICAL   BASIS   OP   PHYSIOLOGICAL   PROCESSES 

To  ascertain  the  nature  of  the  charge  various  methods  may  be  em- 
ployed, of  which  the  following  are  important: 

1.  The  method  of  electrophoresis.  The  colloid  solution  is  placed  in  a 
U-tube,  each  side  of  -which  carries  a  platinum  electrode  dipping  into  the 
solution.  After  a  strong  continuous  electric  current  has  been  allowed 
to  pass  for  some  time  through  the  solution,  it  will  be  found  that  the 
colloid  collects  at  the  anode  (where  the  current  enters)  when  it  is  a 
negative  colloid  (since  unlike  electric  charges  attract  each  other),  and 
at  the  cathode  when  it  is  positive.  In  the  case  of  colored  solutions,  the 
migration  can  be  readily  seen,  but  otherwise  it  may  be  necessary  to  ana- 
lyze the  solution  at  the  two  poles. 


Fig.  15. — Capillary  analysis  of  colloids.  Strips  of  filter  paper,  after  being  suspended  with 
the  lower  ends  dipping  into  colloidal  solutions.  Those  on  the  right  hand  were  positive  colloids, 
which  did  not  rise  in  the  strips,  but  formed  a  sharp  line  of  demarcation  at  the  lower  end  on 
account    of    precipitation.      Those    on    the    left    hand    were    negative   colloids.       (From    W.    Ostwald.) 

2.  The  method  of  capillary  analysis.  For  this  purpose  a  long  strip  of 
filter  paper  is  arranged  vertically  over  the  solution,  with  its  lower  end 
dipping  into  it,  In  the  case  of  negative  colloids  the  colloid,  as  well  as 
the  dispersion  medium,  rises  uniformly  on  the  strip  of  paper  (it  may  be 
to  a  height  of  20  cm.)  ;  Avhereas  with  positive  colloids  the  dispersion 
medium  alone  rises,  the  colloid  itself  doing  so  only  to  .a  very  slight  ex- 
tent, but  becoming  so  highly  concentrated  at  the  interface  between  the 
solution  and  the  paper  that  it  coagulates  on  the  end  of  the  strip  of  paper, 
where  it  forms  a  sharp  line  of  demarcation  (Fig.  15). 

3.  The  method  of  mutual  precipitation  of  colloids.     When  a  positive 


COLLOIDS  57 

and  a  negative  colloid  are  mixed  in  such  proportions  that  the  electric 
charges  are  neutralized,  precipitation  usually  occurs.  When  it  does  so, 
we  can  tell  the  nature  of  the  electric  charge  of  an  unknown  colloid  l>y 
its  behavior  when  a  colloid  of  known  electric  sign  is  added  to  it.  For 
example,  if  ferric  hydroxide  (positive)  causes  a  precipitate  to  form 
when  it  is  added  to  an  unknown  colloidal  solution,  the  electric  charge 
of  the  latter  must  be  negative;  if  it  does  not  precipitate  with  ferric 
hydroxide,  but  does  so  with  arsenious  sulphide  (negative),  it  must  be 
positive.  . 

5.  Brownian  Movement. — Like  the  particles  in  fine  mechanical  suspen- 
sions, those  of  colloidal  solutions,  especially  when  examined  ultra- 
microscopically,  exhibit  the  so-called  Brownian  movements,  which  have 
been  described  as  "dancing,  hopping  and  skipping."  These  movements 
occur  in  straight  lines,  which  are  suddenly  changed  in  direction  and 
are  quite  independent  of  external  sources  of  energy,  such  as  change  in 
temperature  (although  they  become  quicker  as  the  temperature  of  the 
solution  is  raised),  earth  vibrations,  chemical  changes,  or  the  electric 
charge  of  the  colloid.  The  movements  become  more  rapid  the  smaller  the 
particles,  and  they  become  sluggish  as  the  viscosity  of  the  solution  in- 
creases. Addition  of  electrolytes  decreases  the  movement  by  causing  the 
particles  to  clump  together.  The  density  and  viscosity  of  the  disper- 
sion medium,  the  electric  charge  of  the  dispersoid  and  the  presence  of 
BroAvnian  movements,  are  the  forces  which  operate  together  to  prevent 
sedimentation  of  the  particles  in  a  colloidal  solution. 

6.  Osmotic  Pressure. — As  one  of  the  distinguishing  properties  of  col- 
loids we  have  seen  that  their  diffusibility,  as  into  gelatin  or  agar  jel- 
lies, is  extremely  slow  when  compared  with  that  of  a  molecular  solution. 
This  does  not  mean,  however,  that  colloids  are  possessed  of  no  powder  of 
diffusibility  if  left  long  enough.  Indeed  the  existence  of  the  Brownian 
movement  indicates  that  such  diffusion  must  occur,  and  therefore  it 
should  be  possible,  by  the  application  of  the  same  principles  as  those 
which  govern  molecular  solutions  (e.  g.,  by  using  a  semipermeable  mem- 
brane), to  measure  the  osmotic  pressure. 

Many  studies  of  the  osmotic  properties  of  colloidal  solutions  have  been 
undertaken,  especially  by  those  who  are  interested  in  the  possibility 
that  the  colloids  of  blood  serum  (serum  albumin  and  globulin)  may  cre- 
ate an  osmotic  pressure.  If  this  should  prove  to  be  the  case,  it  would 
be  necessary  for  the  osmotic  pressure  to  be  overcome  by  mechanical 
pressure  such  as  that  supplied  by  the  heart  (i.  e.,  the  blood  pressure)  in 
the  various  physiologic  processes  of  filtration  and  diffusion  taking  place 
through  cell  membranes  (as  in  the  formation  of  urine  in  the  kidney). 

For  measuring  the  osmotic  pressure  of  colloids,   osmometers  similar 


58  PHYSICOCHEMICAL    BASIS    OF    PHYSIOLOGICAL   PROCESSES 

to  those  already  described  (page  4)  can  be  employed.  Most  of  the 
recent  work  has  been  done  either  with  collodion  sacs,  or  with  unglazed 
clay  cups  impregnated  with  some  gel,  such  as  silica  or  gelatin.  When 
such  an  osmometer,  filled  with  some  colloidal  solution  (like  a  solution  of 
pure  albumin)  and  provided  with  a  vertical  glass  tube,  is  placed  in  an 
outer  vessel  containing  water,  the  fluid  will  be  seen  to  rise  in  the  ver- 
tical tube,  the  height  to  which  it  rises  being  proportional  to  the  osmotic 
pressure. 

But  the  observed  pressure  does  not  necessarily  give  us  the  osmotic 
pressure  of  the  pure  colloid,  for  to  this,  even  when  highly  purified,  there 
is  almost  certain  to  be  attached  a  considerable  amount  of  inorganic 
salt,  which  may  be  responsible  for  the  osmosis.  It  has  indeed  been 
maintained  by  some  observers  that  electrolytes  form  an  integral  part 
of  certain  colloids,  being  bound  to  them  perhaps  by  adsorption  (see 
page  65),  and  that  they  are  essential  to  the  maintenance  of  the  colloidal 
state.  In  any  case,  since  electrolytes  are  always  present,  the  osmotic 
pressure  of  the  pure  colloid  can  be  measured  only  when  means  are 
taken  to  discount  their  influence.  Several  devices  have  been  used,  of 
which  the  following  may  be  mentioned: 

1.  Addition  to  the  fluid  outside  the  osmometer  of  a  percentage  of 
salt  equal  to  that  found  by  chemical  analysis  to  be  present  in  the  col- 
loid.    (This  method  is  untrustworthy.) 

2.  The  use  of  a  limited  quantity  of  fluid  on  the  outside  of  the  osmom- 
eter so  that  equality  of  saline  content  soon  becomes  established,  by 
diffusion,  in  the  fluids  on  the  two  sides  of  the  membrane. 

3.  The  use  of  a  membrane  which  is  permeable  to  electrolytes  but 
not  to  colloids. 

Even  when  the  greatest  care  is  taken  in  its  measurement,  the  osmotic 
pressure  of  a  given  colloid  has  been  found  to  vary  considerably  not 
only  according  to  the  method  used  in  its  preparation,  but  also  accord- 
ing to  the  amount  of  mechanical  agitation  (shaking,  stirring,  etc.)  to 
which  the  colloid  solution  has  been  subjected.  Regarding  the  influ- 
ence of  the  method  of  preparation,  it  was  found  in  one  series  of  experi- 
ments that  albumin  that  had  been  repeatedly  washed  (but  still  con- 
tained considerable  ash)  gave  no  osmotic  pressure,  Avhereas  another 
preparation  that  had  been  purified  by  crystallization  twice  (and  con- 
tained much  less  ash)  had  a  pressure  of  3.38  mm.  Hg.  According  to 
these  results  the  ash  content  of  the  colloid  is  not  fundamentally  re- 
sponsible for  its  osmotic  pressure.  As  to  the  influence  of  mechanical 
agitation,  the  osmotic  pressure  of  a  gelatin  solution  is  increased  by 
shaking,  while  that  of  a  solution  of  egg  albumin  is  decreased. 

The  property  upon  which  the  osmotic  pressure  depends  is  undoubtedly 


COLLOIDS  59 

the  state  of  dispersion  of  the  colloid  particles,  and  until  we  know  all  of 
the  factors  which  may  influence  this,  measurements  of  osmotic  pressures 

of  colloids  can  scarcely  he  of  very  much  value.  Nevertheless,  thai  this 
property  has  some  physiologic  bearing  is  clear  from  the  effect  which  col- 
loids have  in  restoring  the  blood  pressure  after  hemorrhage   (page  141). 

Further  evidence  that  the  osmotic  pressure  of  colloids  lias  not  the 
significance  that  it  has  in  the  case  of  molecular  solutions  is  furnished  by 
the  fact  that  the  osmotic  pressure  is  only  approximately  proportional 
to  the  concentration  of  the  solution;  it  may  either  increase  or  decrease 
relatively  to  the  strength  of  the  solution.  Temperature  also  has  quite 
a  different  influence  on  the  osmotic  pressure  of  colloids  from  that  which 
it  has  on  the  osmotic  pressure  of  molecular  solutions,  and  it  frequently 
has  an  influence  which  persists  after  the  solution  is  brought  hack  to  its 
original  level. 

The  influence  of  added  suhstances  on  the  osmotic  pressure  of  colloidal 
solutions  is  of  considerable  interest  to  the  biologist,  for,  whereas  in  the 
ease  of  molecular  solutions  this  is  purely  additive,  in  the  case  of  col- 
loids the  added  suhstance  may  at  one  time  cause  the  osmotic  pressure  to 
increase,  at  another,  to  decrease.  It  has  been  found  that  the  osmotic 
pressure  of  gelatin  solutions  at  first  decreases,  then  rapidly  increases  as 
the  H-ion  concentration  is  raised.  The  addition  of  alkali  increases  the 
osmotic  pressure  until  a  maximum  is  reached,  beyond  which  it  begins  to 
fall.  Both  acids  and  alkalies  lessen  the  osmotic  pressure  of  egg  albu- 
min. Electrolytes  always  decrease  the  osmotic  pressure  of  gelatin  and 
albumin  solutions,  and  the  degree  to  which  they  exert  this  influence 
depends  on  the  nature  of  the  cation  and  anion  composing  the  electrolyte. 
In  the  order  of  their  depressing  influence  the  cations  arrange  them- 
selves: 

Heavy  metals  >  alkaline  earths  >  alkalies; 
and  the  anions: 

S04  >  CI  >  N02  >  Br  >  I  >  CNS. 

The  influence  of  a  given  electrolyte  varies  extraordinarily  with  the  reac- 
tion of  the  colloid,  a  fact  which  must  be  carefully  regarded  in  all  work 
in  this  field. 


CHAPTER  VIII 

COLLOIDS  (Cont'd) 

SUSPENSOIDS  AND  EMULSOIDS 

According  to  whether  colloids  form  solutions  that  are  more  or  less 
viscid  than  the  suspension  medium,  they  are  divided  into  emulsoids  and 
suspensoids.  Examples  of  the  former  class  are  silicates  and  gelatin,  and 
of  the  latter,  dialyzed  iron  and  arsenious  sulphide.  The  following  char- 
acteristics are  used  to  distinguish  between  suspensoids  and  emulsoids: 

1.  Measuring  the  time  it  takes,  at  a  standard  temperature,  for  a  given 
volume  of  the  fluid  to  flow  out  of  a  standard  pipette  (10  c.c.)  shows  the 
viscosity  to  be,  roughly,  inversely  proportional  to  the  time  of  outflow.  In 
the  case  of  suspensoids  the  viscosity  is  no  different  from  that  of  the 
dispersion  medium  alone,  and  does  not  vary  much  when  the  solution  is 
cooled.  The  viscosity  of  emulsoids  even  in  very  dilute  solutions  is,  on 
the  other  hand,  considerably  greater  than  that  of  the  dispersion  medium 
itself,  and  it  becomes  greatly  increased  by  cooling. 

2.  Suspensoids  are  much  more  readily  coagulated  by  the  addition  of 
electrolytes  than  emulsoids.  This  is  particularly  true  when  water  is 
the  dispersion  medium  (so-called  hydrosols),  and  when  electrolytes  hav- 
ing a  polyvalent  ion  (such  as  Al  or  Mg.)  are  employed.  Thus,  practically 
all  suspensoids  are  coagulated  in  the  presence  of  1  per  cent  of  alum, 
which  has  no  influence  on  emulsoids.  We  shall  return  to  this  phase  of 
our  subject  later  on. 

The  division  of  colloids  into  emulsoids  and  suspensoids  is  more  or  less 
arbitrary,  since  one  class  may  be  changed  into  the  other,  the  determining 
factor  being  the  water  content  of  the  dispersoid.  The  water  content  of 
suspensoids  is  low  (lyophobe),  while  that  of  emulsoids  is  high.  By 
changing  the  relative  amounts  of  water  and  solid  of  which  a  colloidal 
solution  is  composed,  the  nature  of  the  dispersoid  may  be  changed.  If 
the  water  is  diminished,  the  dispersoid  behaves  as  a  suspensoid  and  be- 
comes readily  precipitated.  The  practical  importance  of  this  fact  is 
that  it  explains  the  salting  out  of  proteins — a  process  extensively  used 
in  their  separation.  Ordinarily  these  behave  as  emulsoids,  but  the  addi- 
tion of  salt  raises  the  osmotic  pressure  of  the  dispersion  medium,  and 
thus  attracts  water  from  the  dispersoids,  with  the  result  that  they  come 

60 


<  ni.i.oms 


61 


to  behave  as  suspensoids,  and  arc  accordingly  precipitated  by  the  elec- 
trolytes. 

Another  property  of  emulsoids  of  biological  importance  is  the  pro- 
tection which  they  can  afford  against  the  precipitating  influence  of 
electrolytes  on  suspensoids.  If  a  colloidal  solution  of  gold  is  mixed  with 
a  trace  of  gelatin,  the  subsequent  addition  of  salts  will  be  found  to 
produce  no  precipitation.  The  explanation  of  this  is  that  the  emulsoid 
becomes  distributed  as  a  film  on  the  suspensoid  particles,  thus  practically 
converting  them  into  emulsoids. 

Gelatinization 

One  of  the  best  known  properties  of  emulsoids  is  that  of  gelatiniza- 
tion, which  has  an  interesting  bearing  on  many  problems  of  biology. 
After  the  gel  has  set,  an  enormous  pressure  is  required  to  squeeze  out 
any  water  from  it,  indicating  that  the  water  no  longer  forms  the  con- 
tinuous phase  but  must  be  enclosed  in  vesicles  formed  of  more  solid 
material. 


B 
Fig.    16. 

As  a  gelatin  solution  cools,  the  gel  at  first  forms  a  polarized  cone  of 
light,  but  the  very  fine  particles  which  are  responsible  for  this  effect 
soon  increase  in  number  and  size  so  that  they  obstruct  one  another  in 
their  Brownian  movements  and  adhere,  giving  an  appearance  of  fine 
felt-like  threads  throughout  the  solution.  A  sort  of  impervious  sponge 
work  of  the  more  solid  phase  is  therefore  formed,  the  more  fluid  phase 
being  inclosed  in  the  meshes. 

If,  as  in  the  accompanying  diagram,  the  dispersion  medium  is  repre- 
sented by  white  and  the  dispersoid  in  black,  the  relationship  between 
the  two  in  a  suspensoid  is  as  in  A,  and  that  in  a  gel  as  in  B.  To  express 
any  of  the  dispersion  medium  in  B,  it  will  require  a  pressure  sufficient  to 


t>2  PHYSICOCHEMICAL    JJASIS   OP   PHYSIOLOGICAL    PROCESSES 

cause  the  more  fluid  phase  to  penetrate  the  more  solid.  If  the  gel  is 
treated  with  reagents  like  formaldehyde,  the  liquid  can  bo  readily  pressed 
out.     This,  occurs  during  fixation  for  histological  purposes. 

Imbibition 

Closely  related  to  gel  formation  is  the  process  of  imbibition — the 
power  of  taking  up  large  quantities  of  water  without  actually  forming 
liquid  solutions.  Besides  gelatin  the  dried  tissues  of  plants  and  animals 
exhibit  the  phenomenon,  and  it  is  undoubtedly  of  importance  in  many 
physiologic  processes  such  as  growth  and  the  passage  of  water  into 
cells,  etc.  The  materials  present  as  vacuoles  in  plant  cells  attract  water 
from  the  environment  of  the  cell  by  imbibition,  and  thus  exert  on  the 
cell  wall  a  pressure  which,  acting  along  with  the  osmotic  pressure, 
maintains  the  turgor  of  the  cell.  The  initial  growth  of  pollen  is  also 
dependent  upon  imbibition,  and  important  observations  on  this  process 
under  varying  conditions,  are  likely  to  furnish  us  with  useful  informa- 
tion concerning  the  significance  of  imbibition  in  connection  with  growth 
of  cells  in  general. 

By  measuring  the  rate  of  increase  in  length  of  long,  narrow  strips  of 
gelatin  placed  in  Petri  dishes  containing  solutions  of  varying  composi- 
tion, the  factors  that  influence  the  imbibition  process  can  be  quantita- 
tively investigated.  Working  in  this  way,  F.  H.  Lloyd17  has  found  that 
for  all  acids  there  is  a  certain  concentration  (about  N/320  H2S04)  which 
induces  a  maximum  rate  of  swelling,  and  another,  much  weaker 
(N/2800  H2S04),  in  which  the  rate  of  swelling  is  even  less  than  in  pure 
water.  In  higher  concentrations  of  acid  than  N/320,  the  gelatin  at  first 
swells  very  quickly,  but  the  rate  slows  off  so  that  it  soon  comes  to  be 
less  than  that  with  intermediate  concentrations.  Regarding  alkalies, 
at  high  concentrations  the  effect  is  similar  to  that  of  acids.  Salts  alone 
seem  to  repress  the  swelling  below  that  of  water.  It  should  be  pointed 
out  that  the  concentrations  of  acid  and  alkali  in  the  above  observations 
are  much  greater  than  those  that  could  occur  in  the  animal  body.  The 
experiments  recall  the  attempts  made  some  years  ago  by  Martin  Fischer 
to  explain  edema  as  due  to  excessive  imbibition  of  water  by  the  pro- 
teins of  the  tissues  because  of  increased  acidity  of  the  blood  and  tis- 
sue fluids.  That  imbibition  might  possibly  play  some  role  in  such 
processes  is  not  denied,  but  Fischer  disregards  entirely  the  now  well-estab- 
lished facts  that  hydrogen-ion  concentration  is  one  of  the  most  constant 
properties  of  the  blood,  that  very  low  concentrations  of  acid  may  dimin- 
ish rather  than  increase  imbibition,  and  that  it  is  manifested  only  in 
the  absence  of  inorganic  salts.*    Moreover,  the  fluid  in  edema  can  often 


'Determinations  of  the  hydrogen-ion  concentration  of  the  blood  recently  published   from   Fischer's 
laboratory  do  not  inspire  confidence. 


COLLOIDS  G'.\ 

be  drained  off  by  hollow  needles,  and  it  passes  by  gravity  From  one  part 
of  the  blood  to  another,  neither  of  which  processes  would  he  possible 
if  imbibition  were  the  essential  factor  concerned.  If  further  evidence 
againsl  this  hypothesis  should  be  demanded,  it  might  be  found  in  the 
utter  failure  of  the  therapeutic  measures — alkali  administration — that 
are  recommended  to  combat  the  edema. 

Action  of  Electrolytes  on  Colloids  (apart  from  their  effect  on  osmotic 
pressure).— It  has  been  stated  above  that  the  charge  which  a  colloidal 
particle  assumes  may  be  neutralized  by  a  charge  of  opposite  si^n  car- 
ried by  an  ion  present  in  the  dispersion  medium.  The  neutralization 
of  the  electric  charge  causes  coagulation  of  the  suspensoids  but  not  of 
the  emulsoids.  Of  the  positive  and  negative  ions  into  which  the  elec- 
trolytes dissociate,  the  one  producing  the  coagulation  is  that  which  is 
opposite  in  sign  to  the  electric  charge  of  the  colloidal  particle. 

A  quantity  of  electrolyte  which  is  capable  of  producing  complete  pre- 
cipitation when  added  all  at  once  to  suspensoids  will  be  ineffective  when 
added  in  small  quantities  at  a  time.  This  phenomenon,  which  is  also 
known  to  be  exhibited  when  toxins  and  antitoxins  are  mixed  together,  is 
probably  owing  to  the  fact  that  precipitation  depends  on  inequality  and 
irregular  distribution  of  electric  charges,  a  condition  which  becomes 
established  when  the  electrolyte  is  suddenly  added,  but  not  so  when  it 
is  gradually  added.  The  particles  in  the  latter  case  become,  as  it  were, 
acclimated  to  the  electric  charges  introduced  by  the  addition  of  the 
electrolyte. 

Proteins  as  Colloids. — The  most  prominent  colloids  in  the  field  of  bio- 
chemistry are  the  proteins.  On  account  of  complexity  of  structure, 
however,  certain  factors  intervene  which  render  the  investigation  of 
their  behavior  very  difficult.  As  we  shall  see  later,  proteins  are  made 
up  of  combinations  of  amino  acids,  each  of  which  contains  basic  (NH2) 
and  acid  groups  (COOII).  The  various  amino  acids  are  linked  together 
in  protein  by  the  COOII  of  one  uniting  with  the  NH2  of  another,  with 
the  elimination  of  water — thus.  CO  jOH  +  Hi  HX — but  some  NH2  and 
COOH  groups  are  left  uncombined.  According  to  the  relative  number 
of  these  uncombined  radicles,  the  protein  (or  polypeptid,  page  601) 
will  exhibit  faintly  acid  or  basic  or  neutral  properties.  With  acids,  for 
example,  a  salt  will  be  formed  by  union  with  the  NII2  groups,  which  will 
dissociate  into  the  anion  of  the  acid  and  a  large  organic  cation;  whereas 
with  alkalies  union  will  occur  with  the  COOH  group,  and  the  salt  on 
dissociating  will  form  a  small  cation  of  the  metal  of  the  salt  and  a  large 
complex  anion.  We  may  therefore  obtain  the  protein  with  either  a 
positive  or  a  negative  electric  charge  by  altering  the  chemical  nature  of 


64  PHYSICOCHEMICAL    BASIS    OF   PHYSIOLOGICAL   PROCESSES 

the  fluid  in  which  it  is  dissolved,  so  that  the  reaction  towards  other 
colloids  and  towards  electrolytes  will  vary. 

One  feature  of  proteins  of  importance  in  this  connection  is  that  known 
as  the  isoelectric  point,  at  which  the  protein  exists  -with  a  maximum  of 
electrically  neutral  molecules.  This  point  is  reached  by  adding  acid  to 
a  protein  solution.  The  acid  represses  the  dissociation  of  the  protein 
acting  as  an  acid,  and  therefore  diminishes  the  number  of  free  hydrogen 
ions;  and  at  the  same  time  it  combines  with  the  NIL  groups  and  neutral- 
izes the  basic  characteristics.  The  alteration  in  electric  charge  thus  in- 
duced alters  the  water-absorbing  powers  of  the  protein  and  therefore 
all  of  the  properties  which  we  have  seen  to  be  associated  therewith 
(page  63). 

SURFACE  TENSION 

Before  we  consider  a  very  important  property  of  colloids  known  as 
adsorption,  by  means  of  which  they  are  able  to  perform  many  reactions 
that  do  not  conform  with  the  laws  of  mass  action,  it  will  be  well  to 


Fig.  17. — Diagram  to  illustrate  surface  tension.  The  rings  A  and  B  inclose  soap  films  in 
which  a  very  fine  loop  of  silk  is  suspended.  In  A  it  is  loose  but  in  B.  where  the  film  inclosed 
in  the  loop  has  been  broken,  it  is  drawn  into  a  circle  by  the  tension  of  the  soap  film.  (From 
Bayliss.) 

say  a  few  words  concerning  the  physical  phenomenon  upon  which  this 
depends — namely,  surface  tension.  The  creation  of  this  force  is  due 
to  the  fact  that,  whereas  the  molecules  within  a  liquid  are  subjected  to 
equal  forces  of  attraction  on  all  sides,  at  the  surface  these  forces  act  on 
one  side  of  the  molecules  only,  and  therefore  tend  to  pull  them  inwards. 
This  causes  the  surface  to  pull  itself  together  so  as  to  occupy  the  least 
possible  area,  and  it  is  this  force  which  constitutes  surface  tension. 
The  surface  behaves  as  if  stretched.  There  are  various  simple  experi- 
ments that  reveal  the  presence  of  surface  tension.  If  a  film  is  made  on 
a  loop  of  wire  by  dipping  it  in  soap  solution,  a  fine  silk  thread  can  be 
floated  in  the  film,  so  that  it  forms  a  loop  that  is  quite  loose.  If  the 
portion  of  the  film  inside  the  loop  is  destroyed  by  touching  it  with  filter 
paper,  the  film  will  break  in  the  loop,  which  will  now  be  pulled  into  a 
circular  shape  by  the  tension  of  the  film  around  it  (Fig.  17). 

For  the   measurement   of  surface   tension,   various   methods   are   used. 


COLLOIDS 


6 


The  size  of  drops  of  liquid  Palling  From  an  orifice  is  dependenl  on  sur- 
face tension;  the  larger  the  drops,  the  greater  the  surface  tension.     II' 
the  number  of  drops  obtained  by  allowing  ;i  liquid  to  drop  from  ;i  stand 
ard  orifice  in  a  given  time  is  ('(united,  we  have  ;i  measure  of  the  surface 

tension.  Account  must  of  course  also  be  taken  of  the  specific  gravity 
of  the  Liquid.  The  instrument  used  for  this  purpose  is  called  ;i 
stalagmometer  (Fig.  IS).  Another  method  depends  on  Hie  fact  thai 
the  heigh.1  to  which  a  fluid  rises  in  a  capillary  tube  is  dependenl  on 
surface  tension  (and  inversely  on  the  diameter  of  the  capillary).  The 
difference  in  the  heights  to  which  two  liquids  rise  in  capillary  tidies  of 
known  bore  permits  ns  to  compare  their  surface  tensions,  and  if  this 
is  known  for  one  of  the  solutions,  it  can  he  determined  for  the  other. 
Besides  existing  between  liquid  and  air,  surface  tension  also  exists  at 
the  interface  between  two  immiscible  liquids,  and  a1   that  between  sus- 


Fib.  18. — Traubc's  stalagmometer.  The  surface  tension  is  proportional  to  the  number  of 
drops  formed  in  a  given  time.  The  right-angled  tubes  are  for  thin  liquids,  and  the  straight 
one    for    blood    and    other    viscous    fluids. 

pended  solid  particles  and  liquid,  as  in  colloidal  solutions.  Since,  as 
we  have  seen,  the  surface  area  (interface)  is  enormously  increased  in 
these  solutions,  a  very  great  surface  energy  is  present,  for  this  is  equal 
to  the  surface  tension  multiplied  by  the  surface  area. 


ADSORPTION 

The  surface  tension  between  liquid  and  air  is  lowered  when  organic 
substances  are  dissolved  in  the  liquid,  but  is  slightly  raised  when  inor- 
ganic salts  are  dissolved.  The  degree  of  lowering  varies  markedly  ac- 
cording to  the  organic  substance  dissolved,  being  very  pronounced  with 
bile  salts,  upon  which  fact  the  well-known  (Hay)  test  for  the  presence 
of  bile  in  urine  is  based.    Between  liquid  and  liquid,  as  well  as  between 


66  rilV-l'  iiflliiMlcAl,    HASIS    OF    I'HVSIOLOGICAL    PBCX 

solid  and  liquid,  the  surface  tension  is  always  lowered  by  dissolving  sub- 
gtances  in  thi  liquid.  Now,  at  the  interfaces  between  solid  part  ides  and 
liquid  there  must  be  a  local  accumulation  of  free  surface  energy,  which 
will  be  equal  to  the  surface  tension  multiplied  by  the  surface  (inter- 
face) area.  A  eonstant  tendency  exists  for  such  free  energy  to  he  de- 
creased and,  since  dissolved  substances  have  this  effect,  they  will  become 
concentrated  at  the  interface.  This  is  known  as  the  principle  of  Willard 
Gibhs,  and  it  is  of  fundamental  importance  to  the  biochemist,  because 
on  it  depfiids  the  phenomenon  known  as  adsorption,  which  in  the  ease 
of  colloidal  solutions  may  therefore  be  defined  as  the  local  concentra- 
tion or  condensation  of  dissolved  substances  at  the  interface  between 
the  two  phases.  The  amount  of  substance  concentrated  at  the  interface 
can  be  calculated  by  a  formula  which,  takes  into  account  the  concentra- 
tion of  the  dissolved  substance,  the  temperature,  and  the  surface  tension 
at  the  interface  (the  Gibbs  formula).  After  absorption  has  occurred,  vari- 
ous reactions  of  a  chemical,  electrical  or  purely  physical  nature  (e.g.,  dif- 
fusion) may  follow  at  a  rate  which  depends  on  the  amount  of  the 
condensation. 

Every-day  Reactions  Which  Depend  on  Adsorption 

1.  Decolorization  of  liquids  by  charcoal.  That  no  chemical  reaction  oc- 
curs  in  such  a  case  is  readily  shown  by  the  ease  with  which  the  pigment 
can  be  extracted  from  the  charcoal. 

2.  Adsorption  of  gases  by  such  solids  as  charcoal  and  spongy  platinum. 
Jn  these  cases  there  must  be  greal  condensation,  even  a  liquefaction  of  the 
gas,  during  which  heat  must  be  evolved.  By  adsorbing  oxygen  and  hydro- 
gen, spongy  platinum  causes  these  gases  to  combine  and  form  water.  The 
hemoglobin  of  blood  may  take  up  oxygen  by  a  similar  process. 

3.  Formation  of  solid  surface  films  on  solutions  of  protein,  saponin,  etc. 
The  condensation  may  lead  to  coagulation,  which  explains  why,  if  the 
froth  produced  by  beating  the  white  of  an  egg  is  allowed  to  stand,  it  can 
not  be  again  beaten  into  a  froth,  the  albumin  having  gone  out  of  solution 
by  surface  coagulation. 

An  interesting  phenomenon  depending  on  the  surface  tension  occurs 
when  the  protoplasmic  contents  of  a  ciliated  infusorian  is  pressed  out  in 
water.  A  new  membrane  forms  on  the  protoplasm  because  of  surface  con- 
centration of  all  constituents  which  lower  surface  energy.  By  application 
of  the  principle  of  Willard  Gibbs,  A.  \'>.  Macallum18  concludes  that  not  only 
adsorption,  as  exhibited  in  a  colloidal  solution,  but  also  the  local  accumula- 
tions of  material  often  seen  in  cells,  are  associated  with  changes  in  sur- 
face energy.  His  conclusions  are  based  largely  on  microscopic  studies 
of  various  forms  of  cell  exhibiting  different  degrees  and  types  of  activity, 


COLLOIDS  G7 

and  ingeniously  stained  for  potassium  by  cobalt  hexanitrite.  By  bucIi 
a  means  the  potassium  stains  intense  black.  In  vegetable  cells,  local 
accumulations  of  potassium  occur  cither  near  the  interface  between  the 
clear  ami   the  phloroph yl-cont aining  parts  of   the   eell    (spirogyra)    or 

under  a  portion  of  the  cell  wall   from  which  later  a  protrusion  grows  out 

to  form  the  first  stage  in  conjugation.  The  outgrowth  Erom  the  cell, 
as  well  as  the  accumulation  of  potassium,  may  be  the  result  of  a  low 
surface  tension.     In   unicellular  animal  organisms,  such  as  Vorticella, 

much  less  potassium  is  present,  being  confined  to  tin1  base  of  the  cilia, 
which  Macallum  believes  indicates  that  the  structures  are  produced  as 
an  outcome  of  low  surface  tension. 

In  the  cells  of  higher  animals,  deposits  of  potassium  are  also  localized; 
in  striated  muscle,  for  example,  they  occur  in  a  zone  at  each  end  of  the 
doubly  refractive  band  and  immediately  adjacent  to  the  singly  refrac- 
tive band.  Changes  in  surface  tension,  associated  with  changes  in  the 
distribution  of  potassium,  are  believed  by  many  to  be  responsible  for 
muscular  contraction.  In  nerves  and  nerve  cells,  potassium  is  concen- 
trated at  the  axon  and  at  the  surfaces  of  the  cells.  Interesting  sugges- 
tions are  offered  to  explain  fbe  relationship  among  changes  in  surface 
tension  at  the  terminations  of  axons  (synapses,  terminations  in  gland  and 
muscle  cells)  brought  about  by  the  nerve  impulse  acting  as  a  change  in 
electric  potential.  Surface  condensation  of  potassium  has  also  been 
observed  at  the  lumen  border  of  gland  cells  (pancreas),  and  on  the  lu- 
men surface  of  the  cells  of  the  renal  tubules.  Such  observations  indicate 
in  what  way  surface  tension  may  be  called  into  play  to  control  cellular 
activities.  The  field  is  new  and  almost  unexplored,  but  there  is  already 
much  to  indicate  that  surface  energy  plays  a  most  important  role  in  the 
performance  of  many  cellular  activities. 

Conditions  That  Influence  or  Are  Influenced  by  Adsorption 

Electric  Changes. — Besides  mere  concentration,  other  forces  come 
into  play  to  assist  or  retard  adsorption.  One  of  the  most  important  of 
these  is  electrical.  Most  solids  when  present  as  particles  in  a  fluid  carry 
a  negative  charge  of  electricity,  some  a  positive  one.  In  conformity  with 
the  "Willard  Gibbs  law,  a  constant  tendency  will  exist  for  this  free  energy 
to  be  diminished  by  the  neutralization  of  the  electric  charge.  This  can 
occur  by  deposition  on  the  interface  of  other  particles  carrying  an 
electric  charge  of  opposite  sign  or  by  the  action  of  that  present  on  ions. 
Charcoal  in  suspension  in  water,  for  instance,  has  a  negative  charge. 
If  colloidal  iron,  which  has  a  positive  charge,  is  added  to  the  solution,  it 
will  become  deposited  on  the  charcoal,  as  will  also  the  cations  of  an 
inorganic  salt.     On  account  of  electric   adsorption,  dyestuffs   and  bile 


68  PHYSICOCHEMICAL    BASIS   OF    PHYSIOLOGICAL    PROCESSES 

sails  are  adsorbed  much  more  freely  than  they  would  be  it'  the  process 
depended  solely  on  surf  ace  condensation ;  that  is,  if  the  Gibbs  formula  is 
used  to  calculate  the  adsorption,  it  will  give  values  thai  are  much  below 

those  actually  found. 

If*  the  dissolved  substance  and  the  particles  both  have  the  same  electric 
sign,  adsorption  will  not  occur.  Filter  paper,  for  example,  has  a  nega- 
tive charge  and  can  not  therefore  adsorb  a  negative  dye  such  as  congo 
red  (as  shown  by  the  depth  to  which  it  becomes  stained)  ;  whereas  it 
readily  adsorbs  night  blue,  which  is  positively  charged.  If  the  negative 
charge  of  the  paper  is  lowered,  it  becomes  capable  of  adsorbing  some  of 
the  negative  congo  red.  This  can  be  effected  either  by  placing  the  paper 
in  alcohol  or  by  adding  inorganic  salts  (NaCl)  to  the  water  with  which 
it  is  in  contact.  The  positive-charged  ions  of  Na,  produced  by  dissocia- 
tion, neutralize  some  of  the  negative  charge  on  the  paper,  and  allow  a 
certain  amount  of  adsorption  of  the  negative-charged  congo  red  to  oc- 
cur. As  .would  be  expected,  acids  and  alkalies  are  capable  of  greatly 
altering  the  electric  charges  by  the  II  and  OH  ions  which  they  contribute. 

Chemical  Forces. — If  the  nature  of  the  phase  at  the  surface  of  which 
adsorption  occurs  is  such  that  it  can  enter  into  chemical  combination 
with  the  substance  adsorbed,  reactions  will  occur  that  do  not  obey  the 
laws  of  mass  action.  By  adsorption,  reactions  of  a  certain  type  may  be 
encouraged  over  other  reactions,  even  although  the  necessary  reacting 
substances  may  be  present  in  the  solution  (specific  adsorption).  The 
adsorbing  substance  itself  is  not,  however,  usually  susceptible  of  chem- 
ical change  even  when  it  exists  as  very  minute  particles,  as  in  the  case  of 
colloidal  solutions.  Nevertheless,  adsorption  may  accelerate  chemical 
reactions  by  bringing  together  in  concentrated  form  substances  of  high 
chemical  reactivity.  In  such  cases  the  adsorbing  substance  itself  does 
not  enter  into  the  chemical  reaction,  and  can  be  recovered  at  the  end 
in  an  unchanged  condition.  It  acts  as  a  catalyst  (page  72).  As  we 
shall  see  later,  enzymes  act  in  this  way — i.  e.,  their  rate  of  reaction  is 
controlled  by  adsorption.* 

The  distinguishing  feature  of  such  adsorption  phenomena  is  that  a 
curve  of  the  reaction  (drawn  by  plotting  amount  of  chemical  change 


♦Another  instance  of  the  influence  of  surface  energy  on  the  course  of  chemical  reactions  is  seen 
in  the  accelerative  influence  of  charcoal  on  such  reactions  as  the  oxidation  of  formic  acid,  glycerol, 
etc.      Surface  tension   may   also   cause   retardation  of   chemical    reactions,   as   is   seen   in   the   turbidity 

(due    to    the    separation    of    chloroform)    which    gradually    develops    when    a    *       XaL.C03    solution    is 

-vf  1 

mixed  with   a chloral   hydrate  solution.      The   surface   remains   clear,    because    surface   energy   has 

prevented  tbe  reaction.  .  . 

An  important  effect  of  surface  tension  on  chemical  reactions  is  also  seen  in  the  relationship 
between  it  and  the  absorption  coefficient  of  gases  (volume  of  gas  dissolved  by  unit  volume  of 
liquid).  The  lower  the  surface  tension,  the  greater  the  solubility  of  the  gas.  Oxygen  and  nitrogen 
are,  for  example,  much  more  soluble  in  alcohol,  hydrocarbons  or  oil  than  in  water.  This  shows 
the  futility  of  attempting  to  prevent  the  loss  of  gases  from  fluids  such  as  blood  by  covering  them 
with  oils  or  hydrocarbons. 


COI.I.OIDS  69 

againsl  concentration  of  reacting  substances)   is  a  parabola,  indicating 

that  the  laws  of  mass  action  (page  23)  are  no  longer  followed.  In 
order  to  be  able  to  determine  whether  some  particular  process  as,  for 
example,  a  fermentation  process,  of  the  absorption  of  oxygen  by  blood — 
is  caused  by  adsorption,  we  must  compare  its  curves,  constructed  ac- 
cording to  the  same  principles,  with  the  typical  adsorption  curve.  A 
formula  may  be  used  in  constructing  the  curves.  In  arriving  at  this 
formula,  two  facts  have  to  be  remembered:  (1)  As  adsorption  proceeds 
and  less  and  less  of  the  free  energy  on  the  adsorbing  surface  remains 
to  be  neutralized,  the  reaction  slows  off,  until  equilibrium  is  reached. 
The  more  dilute  the  solution,  the  greater  is  the  proportion  of  its  con- 
tents to  be  adsorbed,  which  means  that  ii'  a  is  the  amount  of  substance 
adsorbed  from  a  certain  solution,  then,  from  a  solution  of  twice  that 
strength,  somewhat  less  than  2  a  will  be  adsorbed — i.  e.,  a  multiplied 
by  some  root  of  2.  Although  the  formula  is  one  belonging  to  the  class 
known  as  parabolic,  it  must  not  be  assumed  that  every  reaction  which 
happens  to  give  such  a  parabolic  curve  (such  as  the  combination  of  02 
with  hemoglobin  under  certain  conditions)  (see  page  383)  must  be  one 
dependent  on  adsorption. 

It  must  be  understood  that  although  the  substance  that  is  removed 
from  a  solution  by  adsorption  is  no  longer  capable  of  contributing  to  the 
conductivity  or  the  osmotic  pressure  of  the  solution,  it  is  nevertheless 
not  so  firmly  fixed  that  it  can  not  be  set  free  again  by  purely  mechanical 
means,  as  by  constant  dilution  of  the  fluid.  If  charcoal  which  has  ad- 
sorbed sugar  is  placed  in  a  dialyzer  made  of  membrane  the  pores  of 
which  allow  Sugar  but  not  charcoal  to  pass  through,  the  sugar  will 
gradually  be  removed  if  the  dialyzer  is  immersed  in  running  water.  A 
certain  equilibrium  exists  between  the  substance  adsorbed  and  the  same 
substance  still  remaining  in  solution.  If  the  latter  is  constantly  dimin- 
ishing by  dialysis,  the  adsorption  compound  must  break  down  to  main- 
tain the  equilibrium.  It  is  clear,  however,  that  the  process  of  removal 
will  be  extremely  slow.  The  ability  of  adsorbed  substances  to  withstand 
removal  by  washing  is  taken  advantage  of  by  nature  in  holding  back 
foodstuffs  in  the  soil. 

Physiologic  Processes  Depending  on  Adsorption 

Instances  in  which  adsorption  undoubtedly  plays  a  most  important 
part  in  physiologic  processes  are  as  follows: 

1.  The  action  of  enzymes  (see  page  71). 

2.  The  combination  of  toxin  with  antitoxin  occurs  according  to  the  laws 
of  adsorption  rather  than  those  of  mass  action.  In  this  case  it  is  im- 
portant to  note  that  when  the  toxin  of  diphtheria  is  added  in  small  sue- 


70  PHYSICOCHEMICAL   BASIS   OP   PHYSIOLOGICAL   PROCESSI.S 

cessive  quantities  to  diphtheria  antitoxin,  more  toxin  is  neutralized  than 
when  the  toxin  is  all  added  at  once.  A  similar  phenomenon  can  also  be 
observed  by  adding  filter  paper  to  eongo  red,  more  of  the  pigment  being 
adsorbed  when  the  paper  is  added  in  small  quantities  than  when  added 
all  at  once.  The  explanation  is  that  relatively  more  adsorption  of  a 
given  substance  occurs  from  a  dilute  than  from  a  strong  solution  (cf. 
page  69). 

3.  The  sensitizing  of  leucocytes  by  opsonins,  as  well  as  the  subsequent 
ingestion  of  bacilli  by  the  sensitized  leucocytes,  both  of  which  follow  the 
course  of  an  adsorption  reaction. 

4.  The  formation  of  adsorption  compounds,  such  as  the  inorganic  salts 
and  proteins  and  the  complex  lecithin  compounds  that  can  be  extracted 
from  egg  yolk  or  brain  tissue.  In  such  compounds  the  laws  of  chemical 
proportion  no  longer  hold,  and  properties  may  be  exhibited  that  are  quite 
different  from  those  of  either  one  of  its  components.  When  yolk  of  egg 
is  extracted  with  ether,  for  example,  a  compound  of  lecithin  with  vitellin 
goes  into  solution,  although  vitellin  itself  is  quite  insoluble  in  ether.* 
There  can  be  no  doubt  that  adsorption  compounds  of  this  character  are 
very  abundant  in  living  cells,  and  that  they  are  constantly  being  formed 
and  broken  down. 


*By  mixing  solutions  of  egg  albumin,  congo  red  and  a  dye  called  fustic  in  the  presence  of 
alum,  the  colloidal  particles  of  which  each  is  composed  run  together  to  form  larger  colloidal  ag- 
gregates, which  hv  ultramicrosconic  examination  can  lie  seen  to  he  composed  of  a  red,  a  yeliow 
and  a  green  colloidal  particle.  The  attractive  force  holding  the  particles  together  is  electric  in 
this  case. 


CHAPTER  IX 

FERMENTS,  OR  ENZYMES 

One  of  the  most  striking  developments  of  modern  research  in  biochem- 
ist t'y  concerns  the  nature  of  enzyme  action.  So  remarkable  are  many  of 
the  facts  that  have  been  brought  to  light  that  it  can  not  fail  to  interest 
every  one  engaged  in  the  study  of  life  phenomena — whatever  the  nature 
of  that  study  may  be — to  know  something  of  the  main  questions  at 
present  occupying  the  attention  of  investigators  in  this  field.  In  this 
chapter  a  brief  survey  will  be  given  of  some  of  these  questions;  no  at- 
tempt will  be  made  at  completeness,  and  only  where  necessary  for  the 
sake  of  example  will  reference  be  made  to  individual  types  of  enzyme 
action. 

The  discovery  by  Buchner  that  an  enzyme  can  be  expressed  from  yeast 
cells  which  is  capable  of  instantly  bringing  about  the  alcoholic  fermen- 
tation of  dextrose  solutions  has  been  responsible  for  a  great  deal  of  the 
modern  advance.  Formerly,  yeast  cells  were  believed  to  bring  about 
alcoholic  fermentation  as  a  result  of  their  growth:  it  was  believed  to  be 
a  life  phenomenon,  or  "vital  process."  Now  we  know  that  yeast  cells 
produce  an  intracellular  ferment  or  endo-enzyme*  to  which  its  sucroclastic 
properties  are  due  and  which  can  act  apart  from  the  cells  that  produce  it. 
It  is  no  great  stretch  of  imagination  to  think  of  all  chemical  reactions 
mediated  by  cellular  activity  as  due  to  a  similar  mechanism,  and  this  thought 
has  led  to  the  hypothesis  that  all  processes  of  intermediary  metabolism  in 
the  animal  and  plant  are  caused  by  enzyme  action.  Before  Buchner 's 
day  we  knew  only  of  the  extracellular  enzymes  (such,  for  example,  as 
the  digestive  ferments),  that  is  to  say,  of  enzymes,  produced  indeed  by 
cells,  but  secreted  from  them  and  acting  outside  their  protoplasm ;  now 
we  must  recognize  intracellular  enzymes  acting  where  they  are  produced, 
in  the  protoplasm  of  the  cell.  But  we  must  not  permit  this  conception  to 
carry  us  too  far.  "Without  further  investigation  we  must  not  imagine 
that  the  riddle  of  life  is  thus  solved. 

As  an  example  of  the  role  which  extra-  and  intracellular  enzymes  are 
supposed  to  play  in  the  animal  economy  may  be  cited  the  metabolism  of 
protein.  Proteolytic  enzymes  are  very  widely  distributed  in  the  active 
tissues  of  the  animal  and  plant.    By  their  agency  in  animal  life,  the  com- 


*The  terms  "ferment"   and   "enzyme"  are   synonymous,   but   the   latter   is  preferable   as   the   noun, 
leaving  the  former  to  be  used  as  the  verb. 

71 


72  PHYSICOCHEMICAL    BASIS    OF   PHYSIOLOGICAL    1'KOCHSSKS 

plex  protein  molecule  is  split  up  to  render  it  absorbable  from  the  intes- 
tine, and  the  tissues  appropriate  from  the  blood  those  of  the  degradation 
products  that  they  require  for  the  construction  of  protoplasm,  which, 
later,  they  decompose  so  as  to  utilize  the  energy  -which  the  organism 
demands.     All  these  processes  are  believed  to  be  the  work  of  enzymes. 

The  Nature  of  Enzyme  Action 

The  changes  brought  about  by  enzymes  can  also  be  accomplished  by 
ordinary  chemical  means,  but  these  have  often  to  be  of  a  very  energetic 
nature  to  accomplish  what  the  enzyme  can  so  quickly  and  quietly 
perform. 

It  is  the  custom  to  regard  enzymes  as  catalysts.  A  catalyst  is  a  sub- 
stance which  accelerates  (or  retards)  a  chemical  reaction  which  in  its 
absence  could  proceed  at  a  different  (usually  slower)  pace.  The  action 
of  catalysts  has  been  aptly  likened  to  that  of  a  lubricant.  A  weight 
placed  at  the  top  of  an  inclined  plane,  so  held  that  the  weight  only  slowly 
slips  down,  has  its  velocity  greatly  increased  if  its  under  surface  be 
oiled.  The  oil  accelerates  the  action  but  does  not  affect  the  ultimate 
result.  Catalysts  do  not  combine  with  the  final  products  of  the  reaction, 
these  being,  as  a  rule,  the  same  as  they  would  have  been  had  no  catalyst 
been  added.  Another  characteristic  is  the  tremendous  amount  of  chem- 
ical change  which  even  a  trace  of  catalyst  can.  induce.  There  are  many 
examples  of  catalysts  in  the  inorganic  world,  among  which  may  be  cited 
the  action  of  spongy  platinum  on  hydrogen  peroxide.  This  substance 
normally  tends  to  decompose  into  water  and  oxygen,  but  if  a  small 
amount  of  spongy  platinum  is  added  to  it,  the  decomposition  is  greatly 
accelerated:  H202  =  H,0  +  O. 

A  very  good  example  of  the  action  of  an  inorganic  catalyst  is  that  of 
the  hydrogen  ion  on  cane  sugar,  or  other  disaccharides,  in  the  presence 
of  water.  It  accelerates  the  hydrolysis.  Cane  sugar  solution  at  room 
temperature  does  not  indeed,  in  sterile  solution,  undergo  any  appreciable 
hydrolysis,  but  at  100°  C.  it  does,  which  leads  us  to  believe  that,  though 
inappreciable,  the  action  also  occurs  at  room  temperature.  By  adding 
a  little  hydrochloric  acid,  or  other  acid  not  having  an  oxidizing  effect 
on  sugar,  we  greatly  accelerate  the  hydrolysis  because  of  the  hydrogen 
ions  present  in  the  acid  solution.  Within  certain  limits  the  rate  of  hy- 
drolysis is  proportional  to  the  amount  of  catalyst  present. 

Enzymes,  like  other  catalysts,  produce  their  action  when  present  in 
very  small  amounts  (e.  g.,  suerase  can  hydrolyze  200,000  times  its  weight 
of  cane  su^iir;  diastase  can  convert  starch  to  sugar  in  a  dilution  of 
1-1,000,000)  and  there  is  a  distinct  relationship  between  the  amount  of 
enzyme  present  and  the  rate  of  the  reaction.     The  final  product  of  the 


FERMENTS,   <>k    ENZYMES  7:! 

reaction  is,  however,  the  same  a1  whatever  rate  it  proceeds,  and  the 
enzyme  does  not  appear  in  the  final  products.  Many  enzymes  such  as 
diastase  can  be  found  unaltered  in  amount  after  they  have  completed 
their  action.  This  is  determined  by  adding  a  Eresh  supply  of  substrate 
(that  is,  of  material  to  be  acted  on),  when  the  enzymic  action  proceeds 
again  in  the  usual  way.  The  same  is  no  doubt  true  for  all  enzymes, 
though  as  yet  it  can  actually  be  proved  for  only  a  few  of  them.  Enzymes, 
therefore,  may  be  defined  as  catalysts  produced  by  living  organisms. 

The  Properties  of  Enzymes 

Although  enzymes  are  examples  of  catalysts,  they  exhibit  many  proper- 
ties that  appear  to  differ  from  those  of  inorganic  catalysts.  It  will, 
therefore,  be  advisable  in  considering  each  quality  to  compare  it  in 
catalysts  and  enzymes,  for  by  this  method  a  much  clearer  conception  of 
the  nature  of  enzyme  action  can  be  gained  (Bayliss*9).  Those  properties 
that  are  strictly  peculiar  to  enzymes  we  shall  consider  later. 

1.  Most  enzymes  are  remarkably  specific  in  their  action,  whereas  inor- 
ganic  catalysts  arc  very  much  less  so.  Thus,  in  the  case  of  the  enzymes 
which  bring  about  inversion  of  disaceharides,  this  specificity  is  clearly 
shown.  There  is  a  special  enzyme  for  each  of  the  three  disaceharides — 
maltose,  lactose  and  cane  sugar — and  one  of  these  can  not  replace 
another. 

Still  more  strikingly  is  this  specificity  of  enzyme  action  demonstrated 
in  the  fact  that  certain  enzymes,  such  as  zymase  (expressed  from  yeast), 
will  act  only  on  bodies  having  a  certain  configuration,  that  is,  having 
their  side  chains  arranged  in  a  certain  way.  Thus,  there  are  two  varie- 
ties of  dextrose  (a  and  /?),  which  differ  from  each  other  solely  in  the 
fact  that  the  side  chains  are  arranged  in  different  positions  with  rela- 
tion to  the  central  chain  of  carbon  atoms.  This  form  of  isomerism  is 
called  stereoisomerism  because  the  two  bodies  rotate  the  plane  of  polar- 
ized light  to  an  equal  degree  in  opposite  directions.  Zymase  acts  on  one 
of  these  but  not  on  the  other,  and  there  are  innumerable  examples  of  the 
same  kind.  Indeed,  of  all  bodies  that  exist  in  two  stereoisomers  only 
one  is  found  in  living  cells  and  it  is  on  this  variety  alone  that  the  enzymes 
in  animals  can  act.  A  similar  specificity  exists  between  certain  drugs  and 
their  pharmacologic  action. 

Specificity  of  action  is  explained  by  supposing  that  a  union  occurs 
between  the  substrate  and  the  enzyme,  and  for  this  union  to  take 
place  the  enzyme  must  possess  a  configuration  which  corresponds  accu- 
rately with  that  of  the  substrate.  The  process  has  been  compared  to  a 
lock  and  key ;  the  key  must  be  shaped  to  fit  the  lock,  or  it  can  not 
operate.     The  specificity  does  not,  however,  in  itself  disprove  the  close 


74  PHYSICOCHEMICAL   15ASIS   OF   PHYSIOLOGICAL    PROCESSES 

relationship  between  enzymes  and  inorganic  catalysts,  for  on  the  one 
hand  there  are  several  enzymes  which  do  not  exhibit  this  property,  and 
on  the  other,  there  are  inorganic  catalysts  which  do.  For  example, 
lipase,  the  fat-splitting  enzyme  of  pancreatic  juice,  decomposes  not  only 
fats  but  to  a  greater  or  less  degree  a  number  of  bodies  of  the  same  gen- 
eral build  (esters),  and  tyrosinase  can  decompose,  not  tyrosin  alone, 
but  all  phenol  compounds.  Conversely,  the  hydrogen  ion — to  the  pres- 
ence of  which  acids  owe  their  catalytic  powers — can  decompose  the  ordi- 
nary esters  (that  is,  of  acids  containing  the  carboxyl  or  COOH  group) 
but  it  has  no  action  on  the  sul phonic  esters.  However,  enzymes  are  cer- 
tainly much  more  specific  in  their  action  than  inorganic  catalysts. 

2.  Temperature  does  not  influence  catalysis  and  enzyme  action  in  the 
same  way.  As  the  temperature  is  raised  in  the  case  of  inorganic  catalysts, 
the  reaction  becomes  about  doubled  in  rapidity  for  each  rise  of  10°  C, 
whereas  in  the  case  of  enzymes  it  becomes  increased  up  to  a  certain  opti- 
mum temperature,  beyond  which,  as  the  temperature  rises,  the  reaction  is 
first  slowed  and  then  disappears  altogether. 

This  peculiarity  of  enzymes  as  compared  with  inorganic  catalysts  need 
not  in  itself  disprove  the  analogy  between  the  two,  because  enzymes  do 
not  form  true,  but  colloidal  solutions.  Colloidal  solutions,  as  wc  have 
seen,  are  really  fine  suspensions  of  ultramicroscopic  particles;  there  is  no 
splitting  into  ions  of  the  dissolved  substance,  as  is  the  case  with  true 
(molecular)  solutions,  but  the  colloid  is  suspended  in  the  water  or  other 
solvent  to  form  a  heterogeneous  system  (page  51),  on  which  account 
the  surface  area  of  the  menstruum  is  enormously  increased.  Rise  in 
temperature  alters  the  extent  of  the  surface  area,  and  thereby  intro- 
duces an  influence  which  progressively  opposes  catalysis. 

Although  inorganic  catalysts  in  molecular  solution  show  no  optimum 
temperature  but  increase  in  activity  in  proportion  as  the  temperature  is 
raised,  inorganic  colloidal  catalysts  may  show  an  optimum  temperature. 
Thus,  spongy  platinum  shows  an  optimum  temperature  in  its  action  on  a 
mixture  of  hydrogen  and  oxygen.  It  has  therefore  been  suggested  that 
it  is  because  they  are  colloids  that  enzymes  exhibit  this  property. 

3.  Inorganic  catalysts  frequently  carry  the  reaction  to  a  further  stage 
than  that  attained  by  the  act  ion  of  enzymes.  For  example,  acid  breaks 
down  the  protein  molecule  much  more  completely  than  do  the  proteolytic 
enzymes.  This  difference  is  perhaps  explained  by  the  fact  that  enzymes 
are  retarded  in  their  activities  when  there  comes  to  be  a  certain  accumu- 
lation of  the  products  of  the  reaction  present,  The  final  stages  in  the 
reaction  may  become  so  slow  as  to  be  almost  inappreciable.  This  de- 
crease in  activity  is  partly  due  to  a  union  between  the  enzyme  and  the 
products  of  its  activity. 


FERMENTS,   OR    ENZYMES  75 

4.  The  velocity  constant  in  the  case  of  inorganic  catalysts  remains  un- 
changed  throughout  th<  reaction,  whereas  in  the  case  of  enzymes  it  oe- 
com.es  either  less  or  greater  as  the  process  proceeds.  When  a  substance  is 
changed  by  catalytic  net  ion,  it  is,  of  course,  constantly  being  diminished 
in  concentration  so  that  less  and  less  of  it  remains  to  be  acted  on.  This 
implies  that  there  are  fewer  molecules  present  for  the  same  amount  of 
catalyst  to  act  on  and  consequently  that  the  amount  changed  in  a  unit 
of  time  is  progressively  less.  At  any  moment,  therefore,  the  rate  of 
catalysis  will  be  proportional  to  the  amount  of  substance  (substrate) 
left.  To  understand  this  we  must  refer  back  to  what  we  have  learned  about 
mass  action.  If  Ave  suppose  that  two  substances  A  and  B  react  to  form 
two  other  substances  C  and  D,  then,  by  the  law  of  mass  action,  the  reac- 
tion will  not  go  on  to  completion  but  will  stop  when  a  certain  equilibrium 
is  reached.  The  reaction  can  be  represented  by  the  equation 
A  +  B<=±C  +  D,  Avhich  means  that  it  proceeds  at  a  rate  proportional  to 
the  reacting  molecules.  In  some  cases  this  reaction  goes  on  until  either 
A  or  B  has  practically  disappeared  (that  is,  the  equilibrium  point  is  very 
near  the  right  of  the  equation),  as  is  the  case  in  the  inversion  of  cane 
sugar: 

C12  H22  Oxl  +  H20  =  CG  H12  06  +  CG  H12  06 

Taking  place  as  it  does  in  an  excess  of  water,  and  there  being  very 
little  tendency  for  this  reaction  to  go  in  the  opposite  direction  (cf.  re- 
versible action)  (page  25),  the  only  thing  which  will  influence  its 
velocity  is  the  concentration  of  cane  sugar ;  in  other  words,  the  velocity 
of  the  reaction  at  any  moment  will  depend  solely  on  the  concentration, 
C,  of  the  material  still  left  undecomposecl.  This  can  be  determined  by 
means  of  an  equation.* 

The  value  of  such  an  equation  is  that  it  gives  us  a  figure  K,  represent- 
ing the  amount  of  inversion  that  would  occur  in  each  unit  of  time  if  the 
cane  sugar  were  kept  in  constant  concentration.  When,  for  example, 
it  is  stated  that  K  for  a  particular  strength  of  acid  acting  on  cane  sugar 
solution  is  0.002,  this  means  that  when  volume,  concentration  of  acid  and 


*If  x  be  the  amount  of  sugar  inverted  in  time  t.  and  if  we  use  a  figure  called  a  constant  C K)  to 
express  the  fundamental  rate  of  the  reaction  (which  will  therefore  be  different  for  different  reac- 
tions), then  — '—-  —  KC.  But  C  can  not  be  the  same  at  any  two  consecutive  periods  of  time,  because 
the  reaction  is  going  on  continuously.     This  renders  it  necessary  to  use  the  notation  of  the  differential 

calculus,   and  we   have-=r-   =   KC.     The   sign   5   indicates  that   the   reaction   is   a   constantly   changing 

St 
one   so   that  5x  and   5t   represent  such   infinitely   small   amounts   that  they   can    not   be  measured.     By 
methods  of  integralion,   however,   it  can  be  shown  that  the  above   equation  may   be  written: 

K  =    To_T  '  log-    nat.     -—-, 

thus   permitting   us   to   find    the   value   of   K    (Ci    C2   being   the   concentrations   of   cane    sugar   at    the 
times  Ti  T2). 

Any  two  determinations  during1  the  course  of  the  reaction  can  be  used  for  calculating  K.  These 
equations  apply  only  to  cases  in  which  but  one  substance  is  changing  (monomolecular  reaction). 
When  two  substances  are  involved,  the   equation  is   more  complicated. 


76  PHYSICOCHEMICAL    BASIS    OF    PHYSIOLOGICAL    PROCESSES 

temperature  are  constant  in  a  mam-molecular  solution  of  sugar,  0.002 
gram-molecule  of  sugar  would  be  inverted  the  first  minute  and  0.002 
gram  each  succeeding  minute,  provided  we  could  keep  the  solution  con- 
stantly a  gram-molecular  one,  that  is,  provided  we  could  add  sugar  just 
as  quickly  as  it  becomes  inverted. 

At  first  sight  it  may  appeal-  of  little  practical'  importance  to  determine 
K.  In  our  present  discussion  concerning  the  nature  of  enzyme  action, 
it  is  however  of  great  value  for,  whereas  with  inorganic  catalysis  K  is 
really  of  constant  value,  with  enzyme  action  it  is  not  so.  Thus,  when 
cane  sugar  is  inverted  by  sucrase — an  enzyme  present  in  the  intestine 
and  in  yeast — the  constant  gradually  rises;  for  most  other  unimolecular 
reactions  mediated  by  enzymes  it  gradually  falls;  for  example,  the  action 
of  trypsin  on  proteins. 

Where  there  is  a  great  excess  of  substance  to  be  acted  on,  in  compari- 
son with  the  amount  of  enzyme  present,  it  will  be  found  that  a  more 
constant  value  than  K  is  obtained  Avhen  we  compute  the  absolute  amount 
of  substance  decomposed  in  a  given  time.  In  such  a  case,  too,  the 
amount  of  change  in  a  given  time  will  be  proportional  to  the  amount  of 
enzyme  present,  indicating  that  some  sort  of  combination  between  en- 
zyme and  substrate  must  be  the  first  step  in  the  fermentative  process. 
This  fact  has  been  noticed  by  us  in  connection  with  the  hydrolysis  of 
glycogen  in  the  liver.  When  there  is  an  excess  of  glycogen  present,  the 
amounts  which  disappear  in  equal  intervals  of  time  after  death  are  the 
same:  when,  on  the  contrary,  there  is  not  much  glycogen,  the  amount 
which  disappears  gradually  declines,  but,  if  K  be  computed  by  the  above 
equation,  it  is  constant. 

To  make  these  facts  clear  it  may  be  well  to  pause  for  a  moment  to 
consider  an  illustration.  The  conditions  obtaining  when  there  is  a  large 
excess  of  substrate  over  enzyme  may  be  compared  to  those  governing 
the  remoA'al  of  a  pile  of  bricks  from  one  place  to  another  by  a  number  of 
men.  The  pile  of  bricks  represents  the  substrate;  the  men.  the  enzyme. 
If  each  man  works  up  to  bis  capacity,  it  is  plain  that  the  number  of 
bricks  transferred  in  a  given  time  will  not  depend  at  all  on  the  size  of 
the  pile  to  be  transferred.  When,  however,  the  pile  of  bricks  trets  small, 
though  the  same  number  of  men  continue  to  work  the  number  of  bricks 
transferred  in  a  given  time  falls  off,  because  the  men  interfere  with  one 
another's  activities  in  securing  their  loads  from  the  pile.  When  a  similar 
stage  is  arrived  a1  in  enzyme  processes.  Ave  have  to  use  the  velocity  con- 
stant to  show  how  much  work  could  be  done  by  the  enzyme  if  the  amount 
of  substrate  were  maintained  of  constant  amount. 

In  the  large  volume  of  recent  work  which  has  been  done  with  the 
object  of  discovering  the  cause  of  these  variations  in  the  velocity  con 


FERMENTS,    OR    ENZYMES  77 

stanl  in  tin1  ease  of  enzymes,  four  important  conditions  have  been  recog 
oized:  ( 1  ">  reversibility;  (2)  gradual  destruction  of  the  enzyme;  (3)  com 
bination  of  the  enzyme  with  products  of  the  reaction;  (4)  autocatalysis. 

Of  these  four  influences  the  only  one  which  could  be  held  accountable 
for  ;ui  increase  in  the  activity  of  the  enzyme  is  autocatalysis;  in  this 
process  the  enzyme  by  its  action  produces  substances  which  intensify 
its  own  activity.  In  some  eases  at  least — for  example,  the  action  of 
invertase  on  cane  sugar — these  are  acid  bodies,  a  moderate  increase  in 
acidity  favoring  the  action  of  this  enzyme. 

The  other  influences  all  tend  to  retard  the  reaction  and  progressively 
lower  the  value  of  K.  Negative  autocatalysis  occurs  when  the  enzyme 
produces  products  which  interfere  with  its  activity.  Gradual  destruc- 
tion of  the  enzyme  and  its  union  with  the  products  of  its  activity  will 
manifestly  also  decrease  its  power.  There  is  plenty  of  evidence  that 
both  of  these  processes  may  occur. 

Reversibility  of  Enzyme  Action 

But  the  most  important  of  all  the  causes  of  retardation  of  enzyme 
activity  is  undoubtedly  reversibility  of  action,  which  is  an  application  of 
the  law  of  mass  action  (page  25).  If  we  take  the  saponification  of  an 
ester,  the  equation  is: 

CH3CH2CH,COOC=H,  +  H20  ^5  CH3CH,CH,COOH  +  OH5OH. 
(ethyl  butyrate)  (butyric  acid)      (ethyl  alcohol) 

The  equilibrium  point  is  not  so  near  the  position  of  complete  hydrol- 
ysis as  in  the  ease  of  the  inversion  of  saccharose ;  in  other  words,  the 
tendency  for  the  bodies  produced  by  the  hydrolysis  to  reunite  and  form 
the  original  substances  is  quite  marked,  so  that  the  reaction  comes  to  an 
end  before  all  the  ethyl  butyrate  has  been  decomposed.  For  some  time 
before  the  equilibrium  point  is  reached,  there  will  have  existed  a  progres- 
sively increasing  opposition  to  the  breakdown  of  the  ester,  as  a  conse- 
quence of  which,  when  enzymes  are  used  to  accelerate  the  reaction,  the 
velocity  constant,  as  determined  by  the  above  equation,  will  gradually 
fall  as  the  reaction  proceeds.  Conversely,  in  a  mixture  of  ethyl  alcohol 
and  butyric  acid  there  is  very  slow  synthesis  to  ethyl  butyrate,  and  here 
again  lipase  accelerates  the  process;  it  induces  a  recognizable  synthesis 
within  a  short  time.  Ethyl  butyrate  is  usually  employed  for  these  ex- 
periments because,  on  account  of  its  odor,  the  ester  is  readily  recognized. 
Thus,  if  the  alcohol  and  acid  be  mixed  alone,  no  ester  will  be  detectable, 
but  if  some  lipase  be  added,  it  will  soon  become  so.  Similar  synthetic 
action  of  lipase  has  also  been  demonstrated  for  mono-  and  tri-olein. 


78  PHYSICOCHEMIOAL    BASIS    OF   PHYSIOLOGICAL   PROCESSES 

It  should  be  clearly  understood  that  pure  catalysts,  such  as  the  hydro- 
gen ion,  in  accelerating  a  reaction  like  the  above,  do  so  equally  in  both 
directions,  so  that  the  position  of  equilibrium  remains  unchanged.  En- 
zymes may,  however,  cause  this  position  to  change  because  of  their  form- 
ing intermediate  combinations. 

The  reverse  phase  of  certain  reactions  is  probably  the  cause  of  at  least 
some  of  the  synthetic  processes  which  occur  in  the  animal  body.  A  great 
difficulty  in  accepting  such  a  view,  however,  is  the  fact  that  the  equilib- 
rium point  of  all  hydrolytic  reactions,  in  the  presence  of  an  excess  of 
water,  is  so  near  complete  hydrolysis  that  very  little  synthesis  can  be 
possible.  That  is  true  so  long  as  the  substance  synthesized  is  soluble, 
but  if  it  is  nearly  insoluble  in  water,  or  if  it  is  immediately  removed 
from  the  site  of  the  reaction  by  diffusion,  or  in  any  other  way,  then  it  is 
obvious  that  it  will  go  on  being  synthesized  by  the  reaction.  Thus,  in  the 
intestine  neutral  fat  is  hydrolyzed  by  pancreatic  lipase  into  fatty  acid 
and  glycerin,  which  are  absorbed  into  the  epithelium,  where  they  again 
come  under  the  influence  of  intracellular  lipase.  This  latter  will  tend  to 
accelerate  the  synthesis  of  neutral  fat  from  the  fatty  acid  and  glycerin 
until  the  equilibrium  point  of  the  system  (fat  acid  +  glycerin  ±±  neutral 
fat  +  H20)  is  again  reached;  but  this  point,  although  it  is  near  the  right 
hand  of  the  equation,  will  really  never  be  reached  for  the  reason  that  the 
neutral  fat,  as  quickly  as  it  is  formed,  will  become  deposited  in  insoluble 
globules  in  the  protoplasm  and  thus  be  removed  from  the  equation.  In 
support  of  this  view  it  has  been  found  that  lipase  is  present  in  intestinal 
mucosa  after  all  traces  of  adherent  pancreatic  juice  have  been  washed 
away.  By  similar  reactions  the  fat  of  the  tissues  becomes  decomposed  to 
fatty  acid  and  glycerin  and  passes  out  of  the  blood  when  the  concentra- 
tion of  fat  in  this  fluid  falls  below  a  certain  level.  Provided  one  of  the 
substances  synthesized  is  insoluble  or  can  in  some  other  way  be  removed 
from  the  reaction,  it  is  plain  that,  even  though  the  equilibrium  point  is 
very  near  to  that  of  complete  hydrolysis,  yet  the  reversion  will  be  suf- 
ficient to  do  all  that  is  required  of  it. 

Eesults  such  as  the  above  have  prompted  many  to  conclude  that  it  is 
by  such  reversible  action  that  all  synthetic  processes  occur  in  the  living 
organism.  But  the  demonstrable  synthesis  of  an  ester  must  not  be  taken 
as  evidence  that  all  other  syntheses  are  explainable  on  the  same  basis. 
For  example,  we  have  seen  above  that  in  the  case  of  cane  sugar  the  equi- 
librium point  in  the  equation  is  so  near  that  of  complete  hydrolysis,  that  no 
measurable  amount  of  cane  sugar  is  formed  when  dextrose  and  levulose  are 
allowed  to  act  on  each  other,  and  that  cane  sugar  does  not  appear 
when  sucrase  is  added  to  the  mixture.  If  instead  of  sucrase  we  take 
another  of  the  sugar  enzymes — namely,  maltase,  which  accelerates  the 


FERMENTS,   OR    ENZYMES  79 

decomposition  of  maltose  into  two  molecules  of  glucose — there  is,  how- 
ever, evidence  of  synthesis  as  a  resull  of  the  acceleration  of  a  reversible 
reaction.    To  understand  these  results  we  mus1  remember  that  ordinary 

dextrose  is  a  mixture  of  two  stereoisomers  designated  a  and  /?.  When 
two  molecules  of  a  dextrose  condense  (that  is,  fuse  togther  with  the 
loss  of  a  molecule  of  water)  maltose  is  formed,  but  when  two  molecules 
of  /?  dextrose  condense  isomaltose  results.  There  is  some  controversy 
as  to  whether  maltose  is  really  responsible  for  the  synthesis  of  a  dextrose 
molecules  to  maltose,  it  being  claimed  by  some  that  this  is  accomplished 
by  another  enzyme,  emulsine.  If  this  were  true  it  would  materially 
minimize  the  importance  of  reversible  action  as  a  factor  in  cellular  syn- 
thesis. The  latest  evidence  goes  to  show,  however,  that  it  is  maltase 
and  not  emulsine  that  is  responsible  in  the  above  ease  (cf.  Bayliss). 

Evidence,  both  direct  and  indirect,  is  also  steadily  accumulating  to 
show  that  enzymes  may  accelerate  the  synthesis  of  proteins.  As  pieces 
of  direct  evidence  we  have:  (1)  the  retardation  of  the  digestive  action 
of  trypsin,  etc.,  which  sets  in  after  the  process  has  gone  on  for  a  time, 
and  (2)  the  recommencement  of  a  digestive  process  apparently  at  an 
end,  if  the  products  of  the  digestion  are  removed  by  dialysis  or  other 
means.  As  direct  evidence  may  be  cited  the  formation  of  synthetic 
products  when  pepsin  is  added  to  concentrated  solutions  of  peptone, 
and  the  diminution  in  the  number  of  small  molecules,  as  judged  by  meas- 
urements of  electrical  conductivity,  when  trypsin  is  added  to  the  prod- 
ucts of  tryptic  digestion  of  caseinogen.  Protamine — a  simple  form  of  pro- 
tein— has  also  been  found  to  be  produced  when  trypsin — obtained  from 
a  mollusc — was  added  to  a  tryptic  digest  of  the  same  protamine.  The 
significance  of  these  facts  in  connection  with  the  metabolism  of  the 
amino  aids  will  be  evident  when  we  come  to  study  this  subject  (page 
598).* 

Specificity  of  Enzyme  Action 

Although  in  all  of  the  above  features  of  enzyme  action  there  is  nothing 
to  contradict  the  view  that  they  are  catalytic  agents,  there  remains  one 
peculiarity  which  at  first  sight  seems  uninterpretable  on  such,  a  basis. 
This  is  with  regard  to  their  often  remarkable  specificity  of  action.  Thus, 
as  we  have  seen,  maltase  can  hydrolyze  maltose  alone  (which  is  com- 
posed of  two  a-dextrose  molecules),  but  not  isomaltose  (composed  of 
/^-dextrose).  This  means  that  mere  difference  in  the  configuration  of 
molecules  is  sufficient  to  alter  the  influence  of  enzymes  on  them.  Since 
such  differences  could  not  influence  that  of  inorganic  catalysts  we  must 

*We  have  been  unable  in  this  laboratory  to  demonstrate  any  synthesis  of  glycogen  when  gly- 
cogenase  is  added  to  a  hydrolysis  mixture  of  dextrine,  maltose  and  glucose  produced  by  the  prolonged 
action   of  glycogenase   on   pure   glycogen. 


80  PHYSICOCHEMICAL    BASIS   OP    PHYSIOLOGICAL    PROCESSES 

explain  the  cause  of  the  difference.  This  has  been  done  on  the  basis 
either  that  enzymes  arc  colloids  or  thai  the  active  (catalytic)  group  of 
the  enzyme  is  attached  to  a  colloid  molecule.     Before  a  substance  can 

be  acted  on,  it  must  combine  with  the  colloid,  which  it  docs  by  the  proc- 
ess of  adsorption  (sec  page  65).  This  can  occur,  however,  only  when 
there  is  a  harmony  between  the  adsorbing  substance  and  the  substance 
adsorbed.  Instances  of  the  specificity  of  adsorption  have  already  been 
given. 

In  support  of  this  view  it  has  been  found  that  of  the  two  proteases, 
a  and  /?,  in  the  spleen,  one  is  adsorbed  but  not  the  other  when  a  solu- 
tion containing  them  is  shaken  with  Kieselguhr.  Furthermore,  when 
solutions  of  invertase  are  shaken  with  certain  inert  powders,  the  in- 
vertase  is  adsorbed  by  some  of  them  but  not  by  others.  In  strong  sup- 
port of  the  adsorption  hypothesis  is  also  the  fact  that  the  same  mathe- 
matical laws  as  apply  in  the  process  of  adsorption  are  obeyed  in  the 
ratio  which  exists  between  the  activity  of  an  enzyme  and  its  concen- 
tration in  the  solution. 

To  sum  up,  then,  catalysis  as  exhibited  by  enzymes  involves  three 
processes:  (1)  contact  between  the  enzyme  and  the  substrate,  which  will  be 
dependent  on  their  rates  of  diffusion;  (2)  adsorption  between  them,  which 
will  depend  on  their  configurations  (cf.  the  lock  and  key  simile)  ;  and 
(3)  the  chemical  change  which  itself  probably  takes  place  in  two  stages. 
In  connection  with  the  third  process,  it  is  probable  that  an  initial  com- 
pound of  a  definite  chemical  nature  is  first  formed,  followed  by  the 
hydrolytic  or  other  chemical  change,  after  which  the  enzyme  group 
becomes  free. 

It  is  very  significant  in  this  connection  to  note  that  in  their  solubil- 
ities there  exists  a  distinct  relationship  between  the  ferments  and  the 
substrates  on  which  they  react.  Thus,  trypsin  is  very  soluble  in  water 
and  acts  on  water-soluble  proteins;  lipase  is  soluble  in  fat  solvents. 

Certain  Peculiarities  of  Enzymes 

Notwithstanding  the  very  strong  case  that  is  made  out  for  the  cata- 
lytic hypothesis,  there  are  certain  facts  which  many  find  it  difficult  to 
make  conform  with  such  a  view.  One  of  these  is  that  dextrose  can 
undergo  three  distinct  and  separate  types  of  decomposition  according 
to  the  enzyme  allowed  to  act  on  it.  These  are  alcoholic  fermentation, 
butyric  acid  fermentation  and  lactic  acid  fermentation.  It  is  difficult 
to  see  how  simple  catalytic  action  can  be  responsible  for  all  three  results. 
The  enzyme  must  not  only  initiate  the  changes  but  also  direct  their 
course. 

Another  peculiarity  is  that  when  certain  enzymes — e.  g.,  rennin,  pep- 


FERMENTS,   OR   ENZYMES  81 

sin,  etc. — are  inoculated  in  animals,  they  cause  specific  antienzymes  to 
appear  in  the  blood  of  the  inoculated  animal.  Thus,  when  antirennin 
scrum  is  added  to  milk  it,  greatly  hinders  clotting  on  the  subsequent 
addition  of  rennin.  It  is  probable  that  powerful  antienzymes  are  pro- 
duced in  the  animal  body  for  the  purpose  of  protecting  the  tissues  from 
attack  by  enzymes.  It  is  on  account  of  the  presence  of  antienzymes 
that  intestinal  parasites  can  exist  in  the  intestine,  and  the  immunity 
from  digestion  which  the  mucosa  of  the  gastrointestinal  tract  enjoys, 
is  believed  to  be  due  to  the  same  cause.  But  there  is  considerable  doubt 
regarding  this  claim.  Fresh  pancreatic  juice  when  injected  into  the 
empty  intestine  digests  its  "walls.  When  food  is  present  in  the  intes- 
tine it  evidently  prevents  digestion  of  the  walls  by  diverting  the  enzyme 
to  itself. 

Types  of  Enzyme 

Having  learned  something  about  the  general  nature  of  enzyme  action, 
we  may  now  turn  our  attention  to  certain  details  that  have  a  practical 
importance.  In  the  first  place,  with  regard  to  nomenclature,  in  the 
earlier  work  each  newly  discovered  enzyme  received  a  name  Avhich  was 
often  quite  inappropriate.  Many  of  these  names  are  retained,  such  as 
pepsin,  trypsin,  ptyalin,  etc.,  but  it  is  now  customary  to  name  the 
enzyme  according  to  the  substance  on  which  it  acts.  This  is  done  either 
by  replacing  the  last  part  of  the  name  of  the  substance  acted  on  by  the 
termination  -ase  (for  example,  the  enzyme  which  inverts  maltose  is  called 
maltase),  or  by  merely  adding  -ase  to  the  name  of  the  substance  acted 
upon  (thus,  the  enzyme  which  hydrolyzes  glycogen  is  called  glycogenase). 

Most  of  the  enzymes  in  the  animal  body  accelerate  hydrolytic  proc- 
esses and  are  classified  according  to  the  chemical  nature  of  the  sub- 
strate on  which  they  work.     Thus,  we  have: 

1.  The  amylases — accelerating  the  hydrolysis  of  polysaccharides,  e.  g., 
ptyalin  (in  saliva),  amylopsin  (in  pancreatic  juice),  glycogenase  (in 
liver),  diastase  (in  malt). 

2.  The  invertases — accelerating  hydrolysis  of  disaccharides,  e.  g.,  malt- 
ase, lactase  and  sucrase  (in  succus  entericus). 

3.  The  proteinases — accelerating  hydrolysis  of  proteins,  e.  g.,  pepsin 
(in  gastric  juice),  trypsin  (in  pancreatic  juice),  erepsin,  intracellular 
proteinases. 

4.  The  lipases — accelerating  disruption  of  neutral  fats,  e.  g.,  steapsin 
(in  pancreatic  juice),  intracellular  lipases. 

5.  Arginase — accelerating  hydrolysis  of  arginin  into  urea  and  or- 
nithin,  (intracellular). 


82  PHYSICOCHEMICAL    BASIS    OF    PHYSIOLOGICAL   PROCESSES 

6.  Urease — accelerating  hydrolysis  of  urea  to  ammonium  carbonate 
(in  many  microorganisms  and  in  the  soy  bean). 

7.  Glyoxylase — converting  glyoxals  into  lactic  acid    (page  GGG). 
Other  enzymes  accelerate  oxidative  processes  and  are  called  oxidases 

and  peroxidases.  Others  bring  about  the  displacement  of  an  amino 
group  by  hydroxyl  (desamidases) .  Others  cause  coagulation  (coagula- 
tive  ferments),  e.g.,  thrombin,  rennin.  One  of  the  enzymes  present  in 
succus  entericus  acts  by  converting  the  zymogen  (trypsinogen)  into  the 
enzyme  (trypsin). 

Enzyme  Preparations 

So  far  it  has  been  impossible  to  prepare  enzymes  in  a  pure  state  al- 
though, being  colloidal  in  nature,  they  are  readily  precipitated  or  ad- 
sorbed along  with  other  colloids. 

Since  most  enzymes  exist  in  cells,  it  is  necessary  to  break  up  the  cells 
in  order  to  isolate  the  enzyme.  This  is  done  in  various  ways.  By  one 
method  the  cells  are  ground  in  a  mortar  with  fine  sand,  then  made  into 
a  paste  with  infusorial  earth  (Kieselguhr),  the  paste  enclosed  in  stout 
canvas  and  placed  under  an  hydraulic  press  at  about  300  atmospheres 
pressure ;  a  clear  fluid  separates  and  this  contains  the  enzymes.  An- 
other way  is  to  freeze  the  tissue  with  liquid  air  and  grind  it  in  a  steel 
mortar  by  means  of  a  machine.  Still  another  and  less  expensive  method, 
and  one  which  we  have  found  most  useful  for  organs  and  tissues,  con- 
sists in  reducing  the  tissue  to  a  pulp  and,  after  sieving  it  to  get  rid  of 
connective  tissue,  etc.,  spreading  the  pulp  on  glass  plates  and  drying 
in  a  slightly  warmed,  dry  air  current.  The  scales  of  dried  material  are 
then  ground  in  a  paint  mill  with  toluene,  and  the  resulting  suspension 
filtered ;  the  powder  which  remains  on  the  filter,  after  thorough  washing 
with  toluene,  is  dried  and  kept  for  future  use.  The  toluene  removes  all 
the  fatty  substances,  so  that  when  shaken  with  water,  etc.,  the  enzymes 
dissolve. 

Conditions  for  Enzymic  Activity 

Reactions  brought  about  by  intracellular  enzymes  are  very  readily 
inhibited  when  there  comes  to  be  a  certain  accumulation  of  their  prod- 
ucts of  action.  Thus,  yeast  ceases  to  ferment  sugar  when  the  alcohol 
has  accumulated  to  a  certain  percentage.  This  action  is  partially  due 
to  a  toxic  action  of  the  alcohol  on  the  cell,  which  paralyzes  its  power  of 
absorbing  the  substance  to  be  acted  on  by  the  intracellular  enzyme.  If 
these  products  be  not  in  some  way  removed,  they  will  ultimately  kill 
the  cell  and  stop  the  fermentation.  We  have  seen  above  how  the  ac- 
cumulation of  products  may  interfere  with  the  activities  of  enzymes  in 


PERMENTS,   OR    ENZYMES  83 

other  ways  in  which  the  enzyme  docs  no1  suffer  destruction,  as  is  shown 
by  the  Pad  thai  it  resumes  its  original  activities  on  removal  of  the 
products. 

Enzymes,  both  intracellular  and  extracellular,  are  very  sensitive  to- 
wards the  inorganic  composition  of  the  medium  in  which  they  are  act- 
ing. For  the  intracellular  enzymes  this  is  what  we  should  expect  when 
we  bear  in  mind  the  profound  influence  of  inorganic  salts  on  the  hear! 
heat  and  on  cell  growth  and  division.  This  influence  of  salts  and  of 
reaction  (acidity,  etc.)  on  the  life  of  the  cell  is  so  pronounced  as  to  lead 
some  observers  to  believe  that  abnormal  cell  multiplication  in  the  body, 
as  in  the  case  of  tumor  formation,  is  due  to  changes  in  the  inorganic 
composition  of  the  tissue  fluids.  Extracellular  enzymes  are  also  very 
susceptible  to  the  influence  of  inorganic  salts  but  more  especially  so 
towards  the  reaction  of  the  solution.  In  terms  of  modern  chemistry 
we  may  say  that  the  concentration  of  II-  and  OH'  ions  has  a  profound 
influence  .on  the  activities  of  enzymes.  Most  of  the  enzymes  of  the  an- 
imal body  perform  their  action  normally  in  the  presence  of  a  slight  ex- 
cess of  OIF  ions,  that  is,  in  faintly  alkaline  reaction.  Indeed  the  only 
exception  of  importance  to  this  is  the  pepsin  of  gastric  juice,  which  nor- 
mally acts  in  an  acid  medium.  An  excess  of  either  Oil'  or  H-  ions 
inhibits  the  activity  of  the  enzyme  and  usually  destroys  it  permanently. 
The  activities  of  enzymes  arc  also  influenced  by  light,  many  of  them 
being  destroyed  by  sunlight;  cells  such  as  microorganisms  are  similarly 
affected. 

Before  being  secreted  the  digestive  enzymes  exist  in  the  cells  which 
produce  them  as  inactive  precursors  called  zymogens.  The  granules  seen 
in  resting  gland  cells  are  of  this  nature.  The  activation  of  the  zymogen, 
or  its  conversion  into  the  enzyme,  occurs  after  it  has  left  the  cell,  and 
this  has  been  considered  as  another  safeguard  to  digestion  of  the  cell. 
Sometimes  the  activation  does  not  occur  until  the  zymogen  has  travelled 
some  distance  along  the  gland  duct,  as  in  the  case  of  the  proteolytic 
enzyme  of  pancreatic  juice.  Till  it  reaches  the  intestine,  this  exists  as 
trypsinogen  (the  zymogen),  but  it  is  here  acted  on  by  another  enzyme- 
like body  produced  by  the  intestinal  epithelium  and  called  enterokinase. 

PHYSICOCHEMICAL  REFERENCES 

(Monographs  and  Original  Papers) 

'Bayliss,  W.  M.:     Principles  of  General  Physiology,  Longmans,  Green  &  Co.,  1915. 
^Philip,  J.  C. :     Physical  Chemistry,  Its  Bearing  on  Biology  and   Medicine,  Arnold, 

ed.  2,  1914. 
sMcClendon,  J.  S.:     Physical  Chemistry  of  Vital  Phenomena,  Princeton   University 

Press,  1917. 
^Starting,  E.  H.:     Principles  of  Human  Physiology,  ed.  2,  1915,  Lea  and  Febiger. 


84  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

^Kahlenberg,  L.:     Jour.  Physical  Cliem.,  .1906,  x,  141. 

eReid,  E.,  Weymouth:     Jour.  Physiol.,  1898,  xxii,  lvi. 

nVilson,  T.  M.:     Am.  Jour.  Physiol,  1905,  xiii,  150. 

sHahlane,  J.  S.,  and  Priestley,  J.  G.:     Jour.  Pliysiol.,  1916,  1,  29(5;  Priestlev,  J.  G  : 

Ibid.,  p.  304. 
sClark,  W.  M.,  and  Lubs,  H.  A.:     Jour.  Bacteriology,  1917,  ii,  1  and  109. 
"Henderson,  L.  J.:     The  Excretion  of  Acid  in  Health  and  Disease,  Harvey  Lectures, 

J.  B.  Lippincott  Co.,  1915,  x,  132. 
^Henderson,  L.  J.:     The  Fitness  of  the  Environment,  Macmillan,  N.  Y.,  1913. 
i2Van  Slyke,  D.  D.:     Jour.  Biol.  Chem.,  1917,  xxx,  289,  347. 
"Lew,  R.  L.,  and  Rowntree,  L.  G.:     Arch.  Int.  Med.,  1916,  xvii,  525. 
"Cullen,  G.  E.:     Jour.  Biol.  Chem.,  1917,  xxx,  369. 

"Palmer,  W.  W.,  and  Henderson,  L.  J.:     Arch,   Int.  Med.,  1913,  xii,  153. 
"Sellards,  A.  W.:     The  Principles  of  Acidosis  and  Clinical  Methods  for  Its  Study, 

Harvard  University  Press,  Cambridge,  1917. 
i^Lloyd,  E.  H.:     Private  communication. 
isMacallum,  A.  B,  :     Surface  Tension  and   Vital  Phenomena.     University  of  Toronto 

Studies,  No.  8,  1912;  also  Ergebnisse  der  Physiologie,  1911,  ii,  598.' 
"Bayliss,  W.  M.:     Enzymic  Action,  ed.  2.     Monographs  in  Biochemistry,  Longmans, 
Green  &  Co. 


PART  II 
THE  BLOOD  AND  THE  LYMPH 

CHAPTER  X 

BLOOD: ITS  GENERAL  PROPERTIES 
By  R.  G.  Pearce,  B.A.,  M.D. 

The  blood,  being  the  carrier  of  the  nutritive  and  waste  substances  of 
the  body's  metabolism,  must  at  one  time  or  another  contain  all  the  ma- 
terials which  compose  the  tissues  in  addition  to  those  which  are  peculiar 
to  the  blood  itself.  It  is  a  very  complex  fluid,  and  all  of  its  constituents 
are  not  fully  known.  Structurally  it  is  composed  of  water  in  which  are 
dissolved  various  gases  and  organic  and  inorganic  bodies,  the  corpuscles 
and  platelets. 

THE  QUANTITY  OF  BLOOD  IN  THE  BODY 

The  most  accurate  method  of  determining  the  volume  of  blood  in 
the  body  is  by  bleeding  and  subsequently  washing  out  the  blood  from 
the  vessels  and  then  estimating  the  amount  of  hemoglobin  in,  the  total 
fluid  (Welcher's  method).  This  method  employed  in  the  case  of  two 
criminals  who  had  been  decapitated  gave  the  weight  of  the  blood  as 
7.7  and  7.2  per  cent  of  the  body  weight.  Bloodless  methods  for  deter- 
mining the  total  volume  of  blood  are  based  upon  the  principle  of  add- 
ing a  definite  quantity  of  a  known  substance  to  the  circulation  and  then 
estimating  its  concentration  in  a  sample  of  blood  withdrawn  from  the 
body  shortly  afterward.  If  the  substance  can  not  leave  the  blood  vessels 
and  does  not  cause  fluid  to  be  withdrawn  from  the  tissues,  the  total  quantity 
of  blood  in  the  body  can  be  calculated  from  the  concentration  of  the 
injected  substance  in  the  blood.  The  most  accurate  methods  based  on 
this  principle  are  Haldane  and  Smith's,  in  which  carbon  monoxide  gas 
is  inhaled  in  a  given  amount  and  the  carbon  monoxide  hemoglobin  sub- 
sequently determined  colorimetrically ;  and  Keith,  Rowntree  and  Ger- 
aghty's,  which  employs  vital  red,  a  dye  of  low  diffusibility.  The  dye 
remains  long  enough  in  the  body  to  be  thoroughly  mixed  with  the 
blood,  and  its  concentration  in  the  plasma  is  determined  colorimetrically 

85 


86  THE   BLOOD    AND    THE   LYMPH 

by  comparing  with  a  suitable  standard  mixture  of  dye  and  serum.  These 
methods  give  the  total  amount  of  blood  in  the  body  as  from  5  to  8.8  per 
cent  of  its  weight,  Meek  has  recently  developed  a  method  in  which  gum 
acacia  is  used.  After  mixing  with  the  blood,  the  concentration  of  this 
substance  is  determined  from  the  calcium  content,  Being  colloid,  none 
of  the  gum  leaves  the  blood  vessels. 

The  newer  methods  have  shown  that  the  volume  of  the  circulating 
fluid  is  maintained  fairly  constant  in  spite  of  influences  tending  to  alter 
it.  The  body  accomplishes  this  by  drawing  upon  the  reserve  fluid  in 
the  tissues  and  by  varying  the  rate  of  water  excretion,  particularly 
through  the  kidneys.  Years  ago  the  doctrine  of  an  increased  amount  of 
blood  in  the  body  (plethora)  gave  rise  to  the  therapeutic  use  of  bleeding. 
Especially  was  this  thought  to  be  useful  in  conditions  which  Ave  now 
recognize  as  chronic  hypertension,  and  which  show  no  increase  in  blood 
volume.  Indeed  variation  in  blood  volume  is  not  common,  although 
plethora  may  occur  in  polycythemia,  chlorosis,  and  anemias,  and  there 
may  be  a  temporary  reduction  in  the  amount  of  blood  in  diseases  in 
which  there  is  a  great  depletion  of  water,  as  in  Asiatic  cholera,  and  fol- 
lowing very  severe  hemorrhage. 

While  the  total  quantity  of  the  blood  in  the  body  does  not  vary  greatly, 
the  concentration  of  its  various  constituents  is  subject  to  distinct  change. 
The  volume  percentages  of  the  corpuscles  and  the  plasma  can  be  approx- 
imately determined  by  allowing  oxalated  blood  to  sediment  or  by  cen- 
trifuging  in  a  graduated  cylinder  by  the  use  of  the  hematocrit.  Such 
methods  are  not  very  reliable,  but  may  yield  some  important  information. 
Normally  '45  to  50  per  cent  of  the  volume  of  blood  is  composed  of  cor- 
puscles. It  varies  more  or  less  directly  with  the  number  of  red  blood 
cells. 

THE  WATER  CONTENT  OF  THE  BLOOD 

.  Since  the  blood  plasma  is  essentially  a  watery  solution,  some  idea  of 
its  water  content  can  be  obtained  by  a  determination  of  the  specific 
gravity.  The  most  accurate  method  for  accomplishing  this  is  to  deter- 
mine directly  the  weight  of  a  given  volume  of  blood  and  compare  it 
with  the  weight  of  the  same  volume  of  water.  Since  this  method  re- 
quires a  rather  large  amount  of  blood,  indirect  methods  using  smaller 
amounts  have  been  devised.  One  of  these  (Ilammerschlag's)  uses  a 
solution  of  chloroform  and  benzol  of  a  specific  gravity  of  about  1.050, 
in  which  a  drop  of  blood  is  suspended  by  delivering  it  cautiously  from 
a  pipette  bent  at  right  angles  near  its  tip.  If  the  drop  sinks,  chloroform 
is  added;  if  it  rises,  benzol  is  added  until  the  drop  remains  suspended. 


BLOOD:    ITS   GENERAL    PROPERTIES  87 

The  specific  gravity  of  the  benzol-chloroform  mixture  is  then  determined, 
and  this  value  is  supposed  to  give  the  specific  gravity  of  the  blood. 

The  specific  gravity  of  the  blood  determined  in  tliis  way  varies  be- 
tween 1.040  and  1.065.  It  is  somewhat  less  after  eating  and  increases 
after  exercise;  it  is  slightly  lower  during  the  day  than  at  night,  and 
the  variation  in  individuals  is  considerable.  The  changes  which  occur 
in  the  specific  gravity  of  the  blood  in  disease  are  chiefly  due  to  variation 
in  the  percentage  of  protein,  since  the  salt  content  of  the  blood  is  rela- 
tively tixed.  It  is  only  when  great  changes  occur  in  the  concentration 
of  the  noncolloidal  salts  that  they  markedly  affect  the  specific  gravity. 

From  90  to  92  per  cent  of  the  plasma  and  from  59.2  to  68.7  per  cent  of 
the  corpuscles  consist  of  water.  Of  the  whole  blood,  from  60  to  70  per  cent 
by  volume  or  about  55  per  cent  by  weight  consists  of  plasma;  and  from 
40  to  30  per  cent  by  volume  or  45  per  cent  by  weight  consists  of  cor- 
puscles. 

THE  PROTEINS  OF  THE  BLOOD 

The  plasma  obtained  by  centrifuging  the  blood  rendered  noncoagula- 
ble  by  oxalates,  hirudin  or  other  means  (see  page  99),  contains  5  to  8 
per  cent  of  coagulable  proteins.  These  proteins  are  serum  albumin, 
serum  globulin,  and  fibrinogen.  They  can  be  separated  from  each  other 
by  the  use  of  acids  and  neutral  salts.  Their  proportion  varies  under  dif- 
ferent conditions,  but  is  approximately  as  follows: 

Fibrinogen    0.15-0.6% 

Scrum    globulin    , 3.8% 

Serum  albumin 2.5% 

The  amount  of  fibrinogen  is  subject  to  the  greatest  variation  (Mathews). 

Fibrinogen 

The  least  soluble  of  the  blood  proteins  is  fibrinogen.  The  plasma  is 
almost  freed  of  it  by  half-saturation  with  sodium  chloride,  or  with  a 
small  amount  of  acetic  acid.  It  is  precipitated  as  fibrin  in  the  process 
of  blood  coagulation  (see  page  99),  and  is  estimated  by  weighing  the 
amount  of  fibrin  which  it  produces. 

Serum  Globulin  and  Serum  Albumin 

Globulins  are  ordinarily  defined  as  being  insoluble  in  distilled  water, 
and  albumins  as  being  soluble.  It  is,  however,  impossible  to  separate 
serum  globulin  and  albumin  satisfactorily  in  this  manner.  The  globu- 
lin obtained  by  dialysis  can  be  returned  to  solution  by  the  addition  of 


88  THE   BLOOD   AND    THE   LYMPH 

a  suitable  amount  of  water,  which  makes  the  salt  adherent  to  the  pre- 
cipitate a  weak  saline  solution.  In  neutral  or  acid  solutions  it  is  coag- 
ulated by  heat  at  about  75°  C.  But  it  does  not  act  as  an  individual  pro- 
tein, since  a  portion  of  it  is  precipitated  by  dialysis  or  by  carbon  diox- 
ide.    Probably  serum  globulin  really  consists  of  two  or  more  proteins. 

The  serum  albumin  remaining  in  solution  after  saturation  with  am- 
monium sulphate  likewise  does  not  represent  a  chemical  entity.  It  is 
possible  by  carefully  heating  the  solution  of  serum  albumin  to  distin- 
guish three  separate  coagulation  temperatures.  This  fact  has  been  in- 
terpreted as  meaning  that  the  serum  albumin  consists  of  at  least  three 
closely  related  proteins. 

Since  the  refractive  index  of  the  blood  depends  primarily  upon  the 
amount  of  protein  present,  it  has  been  taken  as  a  means  of  determining 
variations  in  the  concentration  of  the  proteins.  It  has  been  found  that 
the  concentration  of  the  blood  proteins  varies  somewhat;  during  ex- 
ercise it  is  increased  probably  because  of  the  taking  up  of  water  by 
the  tissues,  and  during  profuse  bleeding  it  is  diminished  because 
large  amounts  of  fluid  are  being  added  to  the  blood  from  the  lymph, 
which  is  relatively  poor  in  proteins.  The  ingestion  of  considerable 
amounts  of  salts  has  been  found  to  reduce  the  concentration  of  the  blood 
proteins  for  a  short  time.  In  pathologic  conditions,  as  in  diabetes,  Avhen 
rapid  changes  in  the  body  weight  due  to  alterations  in  the  diet  are  oc- 
curring, changes  in  the  fluid  content  of  the  blood  are  often  observed. 
Likewise  in  edema  caused  by  faulty  renal  function,  there  may  be  a  re- 
tention of  fluid  in  the  blood  before  there  is  any  indication  of  edema.  The 
hydremic  condition  of  the  blood  can  therefore  be  considered  as  a  useful 
diagnostic  aid  in  determining  the  water  metabolism. 

The  relative  concentration  of  the  proteins  of  the  blood  is  also  of  some 
interest,  especially  since  in  some  diseases  a  considerable  amount  of 
blood  protein  is  lost.  By  refractrometric  methods  it  is  possible  to  sep- 
arate the  globulin  and  albumin  fractions.  Normally  the  total  proteins 
range  between  6.7  and  8.7  per  cent,  of  which  the  albumins  lie  between 
4.95  and  7.7  per  cent,  and  the  globulins  between  1  and  2.54  per  cent.  In 
some  diseases,  as  in  chronic  nephritis,  pneumonia,  and  syphilis,  the 
total  proteins  of  the  blood  are  decreased  and  the  relative  amount  of 
serum  globulin  is  increased  On  the  other  hand,  in  many  mild  infections 
and  chronic  septic  conditions  the  globulin  fraction  may  be  increased 
with  no  change  occurring  in  the  total  protein  content.3 

Our  knowledge  of  the  origin  and  the  function  of  the  blood  proteins  is 
quite  unsatisfactory.  Previous  to  the  discovery  of  amino  acids,  the 
building  stones  of  the  proteins,  in  the  blood  it  was  thought  that  the 
nitrogenous  nutrients  were  converted  somehow  into  blood  proteins  dur- 


BLOOD:    ITS   GENERAL    PROPERTIES  89 

ing  or  immediately  following  their  absorption  from  the  alimentary 
canal,  and  that  the  tissue  cells  were  nourished  from  this  common  pro- 
tein. It  is  now  known  that  the  amino  acids  are  not  immediately  syn- 
thetized  into  blood  proteins  after  their  absorption    from   the   digestive 

system.  The  blood  proteins  are  radically  different  from  the  tissue  pro- 
teins. Substances  which  retard  or  accelerate  nitrogen  metabolism  do 
not  alter  the  relationship  existing  between  the  protein  bodies  of  the 
blood.  This  fact  indicates  that  the  serum  proteins  have  a  function  quite 
independent  of  the  nitrogenous  metabolism  of  the  body.  They  un- 
doubtedly maintain  the  viscosity  of  the  blood  and  assist  in  preserving 
its  neutrality.  Attempts  to  localize  the  site  of  formation  of  the  blood 
proteins  have  not  been  successful.  There  is  some  evidence  that  fibrin- 
ogen is  formed  for  the  most  part  in  the  tissues  of  the  splanchnic  area 
(liver).  It  is  quite  possible  that  the  blood  forms  its  own  proteins,  just 
as  do  other  tissues,  from    the  amino  acids  it  contains. 

THE   FERMENTS   AND   ANTIFERMENTS    OF    THE   BLOOD 

The  blood  plasma  contains  many  of  the  ferments  present  in  the  tissues. 
The  nature  of  these  ferments  has  been  the  subject  of  many  investiga- 
tions in  recent  years,  primarily  because  it  has  been  found  that  they  are 
intimately  connected  with  the  problems  of  immunity. 

Among  the  ferments  the  following  have  been  demonstrated  in  the 
blood: 

Proteases  are  probably  present  normally  in  the  human  blood  serum 
in  small  amounts,  but  they  are  found  in  large  amounts  in  the  white 
blood  corpuscles.  A  protein  foreign  to  the  body  if  injected  into  the 
blood  ordinarily  produces  no  untoward  symptoms,  but  a  second  injec- 
tion following  the  first  by  some  days  will  produce  symptoms  of  poison- 
ing known  as  anaphylaxis.  This  fact  has  led  to  the  assumption  that 
the  injection  of  any  foreign  protein  into  the  blood  promptly  leads  to 
the  appearance  therein  of  specific  proteolytic  enzymes  which  will  digest 
the  strange  protein  into  its  derivatives,  which  are  poisonous.  This 
power  of  the  body  to  produce  specific  proteases  has  been  the  subject 
of  much  research  and  debate,  and  Aberhalden  proposed  a  test  for  preg- 
nancy, for  cancer,  and  for  other  conditions  in  which  he  made  use  of  this 
phenomenon.  He  believes  the  presence  of  placenta  or  tumor  tissue  to 
cause  the  presence  of  proteins  that  bring  about  the  production  of  specific 
ferments  whose  duty  it  is  to  rid  the  system  of  these  substances.  Other 
investigators  fail  to  find  the  specificity  in  proteolytic  action  claimed  by 
Abderhalden,  and  believe  that  proteolytic  ferments  which  are  capable 
of  digesting  foreign  proteins  are  absorbed  from  the   alimentary  canal 


90  THE    BLOOD    AND    THE    LYMPH 

from  the  digestive  juices  (Boldyreff).  Some  investigators  fail  to  confirm 
the  claim  that  the  proteolytic  activity  of  the  blood  serum  is  increased  under 
the  above  conditions. 

Blood  contains  an  antiferment  known  as  antitrypsin.  This  can  be 
removed  from  the  blood  serum  by  several  substances,  among  which  are 
kaolin,  colloidal  iron  and  starch.  Serum  thus  treated  shows  strong  pro- 
teolytic activity  and  autodigestion  will  occur.  In  this  case  there  can  be 
no  question  of  the  specific  origin  of  proteases.  Abderhalden  believes 
that  the  ferments  of  the  blood  of  the  pregnant  woman  are  able  to  digest 
the  placental  tissue.  Human  placental  tissue  has  the  ability  of  absorb- 
ing antitrypsin  and  it  is  very  questionable  as  to  whether  the  test  pro- 
posed by  Abderhalden  is  due  to  the  new  formation  of  ferments  or  to 
the  removal  of  the  antitrypsin  and  the  action  of  the  protease  normally 
present  in  the  blood. 

Nuclein  ferments  are  capable  of  decomposing  nucleic  acid  and  purins 
into  the  simpler  bodies. 

Lipases  have  been  demonstrated  in  the  blood. 

Amylase. — The  presence  of  starch-splitting  ferments  in  the  blood  was 
first  shown  by  Magendie  in  1841,  and  later  Bernard  showed  that  gly- 
cogen or  starch  injected  into  a  vein  produced  glycosuria.  Since  then 
it  has  been  proved  conclusively  that  diastatic  enzymes  are  normally 
present  in  the  blood  and  lymph.  The  source  of  these  enzymes  has  given 
rise  to  much  speculation.  Some  observers  believe  that  they  are  derived 
from  the  amylopsin  of  the  pancreatic  secretion,  while  others  believe  that 
they  are  manufactured  by  the  liver.  Ligature  of  the  pancreatic  ducts 
is  said  to  increase  the  amount  of  amylase,  while  removal  of  the  pan- 
creas may  (Carlson  and  Luckhart)  or  may  not  (Schlesinger)  increase 
the  amylase  of  the  blood.  In  some  forms  of  experimental  diabetes  the 
amylase  of  the  blood  has  been  found  increased,  and  this  is  the  case  in 
human  diabetes  (Myers  and  Killian).  If  this  is  true,  a  cause  for  the 
inability  of  the  diabetic  to  store  up  glycogen  is  found.  In  impairment 
of  renal  function,  there  is  usually  an  increase  in  the  blood  amylase  and 
a  decrease  in  the  urine  amylase.  This  has  been  suggested  as  being  of 
diagnostic  value. 

The  blood  contains  a  feeble  glycolytic  enzyme  capable  of  destroying 
glucose.     It  is  claimed  that  this  power  is  reduced  in  diabetics  (Lepine). 

Catalase  is  found  in  the  blood  and  tissues  generally.  It  has  the  power 
of  liberating  oxygen  from  hydrogen  peroxide  without  any  accompany- 
ing oxidation  process.  Its  physiologic  significance  is  not  known.  It 
is  said  that  the  amount  of  catalase  is  increased  during  excitement  and 
exercise,  and  is  decreased  in  conditions  where  the  body's  activity  is 
lowered.     Its  determination  is  clinically  unimportant  at  present. 


CHAPTEB  XI 

BLOOD:  THE  BLOOD  CELL 
By  R.  G.  Pearce,  B.A.,  M.D. 

THE  RED  BLOOD  CORPUSCLES,  OR  ERYTHROCYTES 

The  most  prominent  function  of  the  blood  is  to  carry  oxygen  to  the 
tissues.  It  owes  this  property  chiefly  to  the  red  blood  cells  which  are 
present  in  large  numbers  (5,000,000  per  c.mm.  of  blood).  These  cells 
are  biconcave  discs,  having  a  diameter  of  about  7.7  p.  They  are  con- 
structed out  of  a  framework  composed  largely  of  lipoidal  material,  in 
the  meshes  of  which  is  deposited  a  substance  called  hemoglobin,  to 
which  the  remarkable  oxygen-carrying  power  of  the  blood  is  due.  Nei- 
ther the  manner  by  which  the  red  cell  carries  its  hemoglobin  nor  the 
intimate  structure  of  the  cell  itself  is  accurately  known.  It  is  com- 
monly believed  that  the  hemoglobin  is  held  enmeshed  in  a  framework 
or  stroma,  or  encased  in  the  cell  membrane.  One  thing  is  certain,  how- 
ever, that  the  union  of  hemoglobin  with  the  stroma  of  the  red  cell  is 
a  fairly  strong  one,  since  mere  fragmentation  of  the  corpuscle  fails  to 
liberate  the  hemoglobin.  The  fact  that  the  framework  contains  a  large 
amount  of  lipoidal  substances  enables  the  corpuscles  to  maintain  their 
shape  and  is  responsible  for  their  characteristic  permeability. 

Hemoglobin  is  a  very  complex  substance  belonging  to  the  group  of 
conjugated  proteins.  By  chemical  means  it  can  be  broken  up  into  a 
simple  globulin  and  a  pigment  hematin,  containing  iron.  When  com- 
pletely saturated,  oxygen  is  present  in  hemoglobin  in  the  proportion 
of  two  atoms  of  oxygen  to  one  atom  of  iron  (Peters) ;  or  401  c.c.  of 
oxygen  can  be  carried  by  hemoglobin  containing  one  gram  of  iron,  the 
molecular  weight  of  the  molecule  being  about  16.069,  or  some  multiple 
thereof  (Barcroft  and  Peters)  (sec  also  p.  397).  At  this  figure  the 
iron  in  the  molecule  would  represent  0.34  per  cent  of  the  total  Aveight 
of  the  molecule.  The  corpuscular  surface  area  has  been  estimated  to 
be  3200  square  meters.  There  is  therefore  a  very  large  surface  avail- 
able for  the  absorption  of  oxygen  from  the  alveolar  air,  as  the  blood 
corpuscles  pass  in  single  file  through  the  capillaries  of  the  lungs. 

Since  the  amount  of  oxygen  which  the  blood  can  carry  depends  upon 
its   hemoglobin   content,   it    is    of   some   importance    clinically   to   have 

91 


92  THE   BLOOD    AND    THE   LYMPH 

methods  of  determining  the  approximate  amount  present,  The  amount 
of  .hemoglobin  present  in  a  quantity  of  blood  is  usually  determined 
colorimetrically  by  comparing  the  color  of  the  blood  with  standard  col- 
ors which  correspond  to  known  strengths  of  hemoglobin.  In  normal 
persons  the  amount  of  hemoglobin  varies  greatly  at  different  ages,  and 
in  order  to  determine  whether  or  not  a  given  blood  contains  more  or 
less  hemoglobin  than  normal,  it  is  imperative  to  consider  the  age.  The 
greatest  variations  occur  between  birth  and  the  sixteenth  year.  After 
the  sixteenth  year  the  blood  in  males  usually  contains  a  larger  amount 
than  that  in  females  (Williamson4).  Instruments  used  in  determining 
the  amount  of  hemoglobin  should  be  standardized  to  give  the  value  in 
grams  hemoglobin  per  100  c.c.  of  fluid. 

The  amount  of  hemoglobin  which  is  present  in  each  corpuscle  in 
terms  of  normal  is  therefore  of  some  clinical  interest,  This  relation  of 
the  number  of  red  cells  to  the  amount  of  hemoglobin  is  known  as  the 
color  index  and  is  computed  as  follows:  The  average  red  count  in  man 
is  5,000,000  to  the  c.mm.,  and  the  average  minimal  amount  of  hemo- 
globin is  taken  as  13.88  grams  in  100  c.c,  of  blood  (=80,  Sahli;  =00, 
Miescher;  =86,  Plesch;  and  110,  Tallquist  methods).  These  relative 
values  give  a  color  index  of  one.  The  percentage  of  normal  red  cells 
divided .  by  the  percentage  of  normal  hemoglobin  present  gives  the 
color  index. 

The  Origin  of  the  Red  Blood  Cells 

In  fetal  life  the  spleen  and  the  liver  are  generally  believed  to  be  re- 
sponsible for  the  formation  of  the  red  blood  cells.  In  extrauterine  life 
this  function  is  taken  over  by  the  red  bone  niarrow.  In  the  primitive 
condition  all  red  blood  cells  are  supposed  to  be  nucleated.  In  extra- 
uterine life  the  nuclei  of  the  red  cells  are  lost,  and  nonnucleated  forms 
are  alone  present  in  the  blood  stream.  In  fetal  life  and  in  certain  path- 
ologic conditions,  the  rate  of  blood  formation  is  so  rapid  that  some 
nucleated  cells  appear  in  the  blood.  The  normal  response  of  the  body 
to  a  loss  of  red  blood  corpuscles  consists  in  an  increased  activity  of  the 
blood-forming  cells  of  the  red  bone  marrow.  It  is  not  easy  to  follow 
the  course  of  the  regeneration  of  the  red  corpuscles  or  to  discover  the 
mechanism  of  their  formation  in  the  bone  marrow,  since  this  tissue  pre- 
sents a  mixture  of  cells  Avhich  are  precursors  of  the  varied  corpuscles 
found  in  the  blood  and  the  identity  of  which  can  not  be  determined. 

Recently  new  methods  of  staining  blood  for  microscopic  examina- 
tion have  allowed  more  detailed  study  to  be  made  on  the  site  and 
method  of  blood  cell  formation.  When  fresh  unfixed  blood  is  treated 
with  solutions  of  various  dyes,  such  as  brilliant  cresyl  blue,  polychrome 


THE    BLOOD   CELL  93 

methylene  blue  or  neutral  red,  an  otherwise  invisible  structure  appears 
in  some  cells  in  the  form  of  coarse  granular  particles  or  threads,  which 
give  a  reticulated  appearance  to  the  corpuscles.  These  reticulated  cells 
are  more  abundant  in  infants'  blood  and  in  patients  suffering  with  se- 
vere anemia  or  hemolytic  jaundice  than  in  normal  blood,  and  may  be 
taken  as  evidence  of  the  youth  of  the  red  cell  and  not  as  a  degenera- 
tive process.  Since  the  number  of  the  reticulated  cells  that  are  presenl 
in  the  blood  is  more  or  less  directly  proportional  to  the  hemopoietic 
activities  of  the  bone  marrow,  enumeration  of  the  reticulated  cells  is 
of  clinical  importance  in  anemias.  In  conditions  in  which  animals  have 
been  made  plethoric  by  the  transfusion  of  blood,  it  has  been  found  that 
the  number  of  reticulated  cells  is  decreased;  the  bone  marrow  of  these 
animals  also  shows  a  marked  reduction  in  reticulated  erythroblasts. 
The  diminished  rate  of  blood  cell  formation  sometimes  noted  after  blood 
transfusions  may  be  explained  by  assuming  that  the  stimulus  which 
awakens  the  formation  of  red  cells  in  the  bone  marrow  is  absent  or 
made  subnormal  on  the  injection  of  red  cells  into  the  blood,  and  thus 
the  formation  of  red  cells  is  depressed.  Small  transfusions  are  there- 
fore preferable  to  large  ones  in  cases  in  which  the  rate  of  blood  forma- 
tion is  greatly  impaired.  By  means  of  living  cultures  of  red  bone  mar- 
row the  different  stages  of  the  development  of  the  normoblasts  into 
true  red  corpuscles  may  be  studied  (Tower  and  Herm5).  Some  evidence 
has  been  gathered  from  such  studies  which  points  to  the  conclusion  that 
in  place  of  the  red  cells  being  cells  which  have  lost  their  nucleus,  as  is 
the  current  teaching,  they  are  rather  cells  which  develop  as  a  nuclear 
bud  and  escape  into  the  circulation  as  true  red  cells.  The  nucleated 
red  cell  and  the  red  nucleated  corpuscle  of  the  bird  are  the  product  of 
intranuclear   activity  and   are   morphologically   identical. 

Rates  of  Regeneration  of  Erythrocytes 

Microscopic  examination  of  the  blood  during  rapid  regeneration  of 
red  cells  shows  the  presence  of  nucleated  forms.  Nucleated  red  cells 
in  the  blood  have  therefore  been  taken  as  an  inevitable  feature  of  rapid 
blood  regeneration.  The  evidence  upon  which  this  belief  depends, 
however,  is  hardly  complete,  since  changes  in  the  manner  of  red  blood 
cell  formation  may  be  responsible  for  the  nucleated  forms.  The  red 
bone  marrow  is  considered  the  seat  of  red  cell  formation,  and  it  is  true 
that  an  abnormal  increase  in  the  red  bone  marrow  usually  accompanies 
increased  red  cell  formation.  The  nature  of  the  stimulus  which  brings 
about  the  new  formation  of  red  cells  is  not  understood.  Oxygen  want 
may  be  an  important  factor,  since  we  find  the  presence  of  an  abnormally 
large  number  of  red  cells  in  conditions  where  there  is  a  scarcity  of 


94  THE   BLOOD   AND   THE   LYMPH 

oxygen  in  the  inspired  air,  as  in  life  at  high  altitudes,  or  a  difficulty  in 
its  absorption  through  the  lungs,  as  in  congenital  heart  disease. 

The  red  cells  produced  following  hemorrhage  and  in  simple  anemia 
contain  less  than  the  normal  amount  of  hemoglobin,  but  their  shape  and 
size  are  approximately  normal,  and  few  nucleated  cells  are  present.  In 
the  regeneration  of  red  cells  which  is  found  in  pernicious  anemia,  Ave 
find  the  cells  containing  an  unusually  large  amount  of  hemoglobin. 
The  red  cells  in  this  disease  have  abnormal  forms,  many  being  large, 
with  or  without  a  nucleus,  and  containing  basic  staining  granules. 
This  type  of  blood  cell  formation  is  due  to  degenerative  changes. 

The  Fate  of  the  Erythrocytes 

The  length  of  life  of  the  red  blood  cell  is  unknown.  Estimates  based 
upon  the  daily  excretion  of  bile  pigments  are  not  reliable,  since  Hooper 
and  Whipple  have  shown  that  the  pigments,  in  part  at  least,  arise  from 
pigments  which  the  liver  has  made  in  excess  of  its  needs  for  the  manu- 
facture of  hemoglobin,  and  which,  not  being  needed,  are  excreted.5 
There  is  no  question  however  that  every  erythrocyte  sooner  or  later 
undergoes  disintegration,  a  process  formerly  thought  to  be  ushered  in 
by  the  ingestion  of  the  red  blood  cell  by  a  phagocyte  in  the  spleen  or 
in  a  hemolymph  gland,  the  hemoglobin  of  the  disintegrated  cell  being  set 
free  and  carried  to  the  liver,  where  it  is  broken  up  into  hematin,  which 
the  body  stores  for  future  use,  and  into  bile  pigments,  which  are  ex- 
creted. Rous  and  Robertson'1  fail  to  find  evidence  that  this  process 
occurs  in  man  to  an  extent  sufficient  to  account  for  the  normal  destruc- 
tion of  the  blood  cells.  However  they  have  recently  found  another  and 
unsuspected  method  for  blood  destruction  in  all  animals  thus  far 
studied — namely,  the  disintegration  of  the  blood  cells  by  fragmentation 
while  they  are  circulating,  without  loss  of  their  hemoglobin.  These 
fragmented  cells  are  found  most  frequently  in  the  spleen.  They  believe 
that  the  small  ill-formed  cells,  known  as  microcytes  and  poikilocytes, 
observed  in  severe  experimental  anemias,  are  due  not  to  the  fact  that 
they  are  produced  by  the  bone  marrow,  but  rather  to  the  fact  that  the 
marrow  in  its  anemic  condition  is  not  able  to  produce  a  resistant  ery- 
throcyte, and  fragmentation  therefore  takes  place  too  readily.  A  sim- 
ilar condition  may  exist  in  the  severe  anemias  of  man  and  account  for 
the  general  high  resistance  of  the  red  cells  found  in  the  blood  of  these 
patients,  inasmuch  as  the  weak  cells  are  generally  fragmented  very  soon 
after  they  are  formed.  Long  ago  Ehrlich  stated  that  the  microcytes 
and  poikilocytes  of  anemia  are  the  result  of  fragmentation  of  the  cells 
in  the  circulating  blood,  but  he  believed  that  this  fragmentation  was  a 


THE  BLOOD  CELL  95 

purposeful  division  in  order  to  increase  the  total  surface  of  the  red 
colls.  The  ultimate  fate  of  the  red  cell  fragments  is  qo1  known.  Ii  is 
reasonable  to  suppose  thai  the  fragmented  bits  containing  hemoglobin 
are  carried  to  the  liver,  where  the  hemoglobin  is  transformed  into 
hematin  and  bile  pigments. 

Hemolysis 

Another  method  of  red  blood  cell  destruction,  which,  however,  dues 
qo1  take  place  "normally,  is  by  hemolysis.  The  nature  of  the  combina- 
tion of  the  hemoglobin  with  the  stroma  of  the  red  cell,  as  already  re- 
marked, is  nol  definitely  known.  That  it  is  not  merely  contained  in  a 
sac  is  shown  by  the  fact  that  the  cell  may  be  cut  into  bits  -without  the 
hemoglobin  being  set  free.  In  some  manner  the  hemoglobin  is  chem- 
ically bound  with  the  stroma  of  the  red  cell,  from  "which  it  can  be 
freed  by  a  number  of  physicochemical  and  chemical  agents.  This  proc- 
ess is  known  as  hemolysis,  and  the  substances  which  bring  it  about  are 
known  as  hemolytic  agents.  The  manner  in  which  these  agents  effect 
the  release  of  hemoglobin  from  the  blood  is  quite  varied. 

If  the  osmotic  pressure  of  the  plasma  is  lowered  by  dilution,  the  pres- 
sure within  the  corpuscle  remains  high,  and  water  is  absorbed  by  the 
cell.  If  this  absorption  is  sufficient,  the  cell  ruptures  and  the  hemoglobin 
is  discharged.  For  this  reason  it  is  necessary  in  diluting  the  blood  to 
use  solutions  of  salt  having  an  osmotic  pressure  equal  to  that  of  the 
blood  to  protect  the  red  cell  from  hemolysis.  This  is  obtained  by  using 
a  0.9  per  cent  solution  of  sodium  chloride.  Better  results  are  had, 
however,  by  using  either  Ringer's  solution  (0.9  per  cent  NaCl,  0.026 
per  cent  CaCl2,  and  0.03  per  cent  KC1)  or  Locke's  solution  (0.9  per  cent 
NaCl,  0.024  per  cent  CaCl2,  0.042  per  cent  KC1,  0.01-0.03  per  cent 
NaHCO,  and  0.1  per  cent  glucose). 

In  normal  corpuscles  hemolysis  occurs  to  a  small  extent  in  solu- 
tions containing  about  0.42  per  cent  of  sodium  chloride.  In  certain 
diseases  the  fragility  of  the  corpuscles  may  be  increased  (Butler7). 

The  membrane  and  stroma  of  the  erythrocyte  contain  lipoidal  ma- 
terial which  is  soluble  in  alcohol,  ether,  fatty  acids,  and  bile  salts. 
Addition  of  these  agents  to  the  blood  brings  about  hemolysis,  presum- 
ably by  dissolving  the  lipoidal  material  present.  The  hemolysis  which 
occurs  with  saponin  is  similar  in  type,  since  saponins  combine  with 
lipoids,  the  compound  being  soluble  in  water. 

The  hemolytic  properties  of  serum,  whether  they  are  found  to  be 
normally  present  when  the  bloods  of  certain  animals  are  mixed  or  to 
be  produced  artificially  by  the  injection  of  foreign  red  cells,  furnish  a 
subject  of  great  interest  from  the  standpoint  both  of  immunology  and 


96  THE   BLOOD   AND    THE   LYMPH 

of'  clinical  medicine.  The  hemolytic  serum  produced  by  the  injection 
of  foreign  corpuscles  owes  its  activity  to  two  substances.  The  one 
called  the  amboceptor,  or  immune  body,  is  specific  against  the  type 
of  cell  injected  and  is  increased  during  immunization.  The  second 
body  is  the  complement ;  it  is  nonspecific,  and  is  not  increased  dur- 
ing immunization.  Complement  is  destroyed  by  heating  the  serum  for 
one  hour  at  55°  C,  leaving  the  amboceptor  alone  present.  Corpuscles 
placed  in  such  serum  are  not  hemolyzed  until  complement  either  from 
fresh  immune  or  from  nonimmune  serum  is  added. 

The  serum  of  animals  possessing  natural  hemolytic  properties  towards 
the  corpuscles  of  other  animals  likewise  owes  its  effect  to  the  joint  action 
of  amboceptors  and  complement. 

Ordinarily  the  serum  from  animals  of  one  species  does  not  exhibit 
hemolytic  properties  to  blood  from  another  animal  of  the  same  species. 
In  unusual  cases,  however,  the  serum  of  an  animal  will  produce  hemol- 
ysis of  the  corpuscles  of  an  animal  of  the  same  species.  Such  sera  are 
said  to  possess  isohemolysins.  The  fact  is  of  great  importance  in  the 
transfusion  of  blood  from  one  individual  to  another. 

The  cause  of  the  acute  hemolysis  which  occurs  in  the  disease  parox- 
ysmal hemoglobinuria  is  not  known.  It  is  probably  due  to  the  presence 
of  a  hemolytic  substance  which  unites  with  the  blood  corpuscles  at 
temperatures  below  the  normal  body  temperature,  since  the  attack  fol- 
lows exposure  to  cold,  and  blood  from  patients  subject  to  the  condition 
may  be  hemolyzed  in  vitro  by  cooling  and  subsequently  heating  it. 

LEUCOCYTES 

There  are  a  number  of  varieties  of  white  cells  in  the  blood.  These  are 
differentiated  from  one  another  by  their  shape,  staining  properties,  and 
the  granules  in  their  protoplasm.  We  may  divide  them  into  two  main 
groups — nongranular  mononuclear  cells  and  granular  polynuclear  cells. 

The  nongranular  mononuclear  cells  are  termed  lymphocytes.  Two  va- 
rieties are  differentiated,  the  small  and  the  large. 

The  small  mononuclear  leucocyte  makes  up  from  23  to  28  per  cent 
of  the  total  leucocytes  and  the  large  mononuclear,  from  2  to  4  per  cent. 

The  polynuclear  leucocytes  are  divided  into  three  groups  according 
to  whether  their  granules  stain  with  basic,  neutral  or  acid  stains.  The 
leucocytes  that  stain  with  basic  dyes,  or  the  basophile  cells,  are  very 
few,  making  up  less  than  one  per  cent  of  the  total  count.  Likewise  the 
acid-staining  granular  cells,  acidophile,  are  few,  comprising  from  2  to 
4  per  cent  of  the  total  count.    The  most  numerous  are  the.  neutrophiles, 


Till;   RI.OOD   CELL  97 

or  the  polynuclear  leucocytes,  with  aeutral-staining  granules.  These 
coin  prise  from  65  to  75  per  cent  of  the  total  count. 

Another  type  of  white  cell  is  known  as  the  transitional  cell,  because 
it  was  supposed  to  represent  an  intermediate  form  between  the  mono- 
Mini  polynuclear  cells.  Probably  such  transitions  do  not  occur,  and  the 
transitional  leucocyte  is  related  to  the  mononuclear  cells. 

The  polynuclear  cells  originate  in  the  bone  marrow,  and  for  this 
reason  have  been  termed  myeloid  cells.  They  develop  from  cells  in 
the  bone  marrow  termed  myeloblasts,  which  are  nongranular  and  con- 
tain a  large  nucleus.  In  the  course  of  development  the  characteristic 
granules  appear,  and  the  nucleus  remains  round  and  later  becomes 
lobulated.  These  intermediate  forms  are  called  myelocytes.  The  mono- 
nuclear cells  originate  in  the  lymphatic  tissues  of  the  body. 

The  leucocytes  possess  the  ability  to  make  ameboid  movement  and 
to  ingest  foreign  particles  which  may  be  presented  to  them.  On  ac- 
count of  this  latter  ability  they  are  commonly  called  phagocytes.  In 
the  process  of  inflammation  the  leucocytes  assemble  at  the  spot  which 
is  the  seat  of  the  injury  or  infection,  and  remove  the  foreign  organism 
or  necrotic  tissue  by  ingesting  and  digesting  it. 

It  is  not  definitely  known  whether  or  not  the  lymphocytes  func- 
tion as  phagocytes.  Other  functions  besides  those  as  phagocytes  have 
been  ascribed  to  the  white  cells,  but  they  are  not  universally  ac- 
cepted. The  number  of  leucocytes  in  the  blood  is  subject  to  con- 
siderable variation.  They  normally  number  between  6,000  and  8,000 
per  c.mm.  At  the  height  of  digestion  and  after  strenuous  exercise 
there  is  usually  a  small  increase,  and  under  pathologic  conditions, 
especially  in  infectious  diseases,  this  becomes  quite  marked.  Some 
infections  increase  the  polymorphonuclear  cells,  while  others  add  to 
the  lymphocytes.  The  factors  governing  the  type  of  increase  are  not 
fully  known,  nor  are  the  functions  of  the  various  forms  differentiated. 

The  Blood  Platelets 

These  are  small  oval  particles  about  3  /x  in  diameter,  which  are  found 
in  large  numbers  (250,000  to  the  c.mm.)  in  the  blood.  They  are  sup- 
posed to  be  formed  from  particles  of  protoplasm  which  are  pinched 
off  from  the  large  blood  cells  in  the  bone  marrow.  Their  biological 
and  chemical  properties  are  not  understood.  They  probably  play  a 
very  important   role   in   the   coagulation   of   the   blood    (see   page    103). 


CHAPTER  XII 
BLOOD:   BLOOD   CLOTTING 

On  leaving  the  blood  vessels,  the  blood  clots  so  as  to  form  a  plug, 
which  assists  in  preventing  further  hemorrhage.  The  clotting  must 
therefore  be  considered  as  a  protective  mechanism  against  excessive 
draining  of  blood  out  of  the  organism.  When  the  wounded  vessels 
are  small,  the  clotting,  along  with  constriction  of  the  damaged  vessels 
and  the  formation  in  them  of  thrombi  containing  large  numbers  of 
platelets,  serves  to  effect  complete  stoppage  of  the  hemorrhage  even 
though  the  blood  pressure  may  not  have  become  materially  reduced. 
The  greater  loss  of  blood  from  larger  vessels  causes  the  arterial  pressure 
to  fall,  and  this  enables  the  clot  to  stiffen  and  seal  the  Avound  before 
the  pressure  again  rises.  When  the  clotting  power  of  the  blood  is 
subnormal,  life  is  endangered  by  even  trivial  wounds ;  under  these 
conditions  the  smallest  surface  scratch  may  continue  to  bleed  exces- 
sively in  spite  of  whatever  local  treatment  is  applied.  The  most  ex- 
treme degree  of  this  condition  occurs  in  hemophilia,  a  disease  which 
is  characterized  by  a  most  interesting  family  history — namely,  that 
although  it  affects  only  certain  of  the  male  members  of  a  family, 
yet  it  is  transmitted  from  generation  to  generation  by  the  female  side 
alone.  The  disease  has  existed  in  certain  of  the  royal  families  of 
Europe  for  many  generations,  which  has  made  it  possible  by  con- 
sulting the  genealogic  trees  to  demonstrate  the  infallibility  of  this 
law  of  inheritance. 

The  clotting  of  the  blood  is  also  either  depressed  or  increased  in  a 
variety  of  physiologic  and  pathologic  conditions.  We  shall,  however, 
defer  further  consideration  of  these  until  we  have  learned  something 
of  the  nature  of  the  factors  which  are  responsible  for  the  process  itself. 

The  Visible  Changes  in  the  Blood  During  Clotting 

In  a  few  minutes  after  it  leaves  the  blood  vessels,  the  blood  forms  a 
jelly-like  clot,  which  adheres  to  the  walls  of  the  container  in  which  the 
blood  is  collected  and  soon  becomes  so  solid  that  the  vessel  may  be 
inverted  without  spilling  any  of  the  blood.  Clotting  is  now  said  to  be 
complete.  The  clot  soon  begins  to  contract,  and  as  it  does  so,  drops  of 
clear  fluid  or  serum  become  expressed  and  float  on  the  surface  of  the 

98 


BLOOD   CLOTTING  99 

clot  or  collect  between  it  and  the  walls  of  the  container,  so  thai  after 
some  time  the  elol  breaks  away  from  the  container  and  comes  to  floal 
in  the  serum.  The  latter  may  be  perfectly  clear,  but  usually  is  more  or 
less  opalescent,  partly  because  of  the  presence  of  fat,  and  partly  be- 
cause of  leucocytes  which  have  migrated  out  of  the  clot  on  account  of 
their  power  of  diapedesis. 

[f  a  drop  of  freshly  shed  blood  is  examined  under  the  microscope,  it 
•will  be  observed  that  the  first  step  in  clotting  consists  in  the  formation 
of  fine  threads  radiating  from  foci,  which  are  undoubtedly  the  blood 
platelets.  The  tine  threads  are  called  fibrin.  They  multiply  rapidly, 
so  as  to  form  an  interlacing  meshwork  which  entangles  the  red  blood 
corpuscles  and  leucocytes.  By  the  use  of  the  ultramicroscope  (page  52), 
Howell1  and  others  have  observed  that  the  fibrin  (produced  by  adding 
thrombin  to  oxalated  plasma)  is  really  deposited  in  the  form  of  fine 
crystalline  needles — "fibrin  needles" — which  become  packed  together 
as  they  increase  rapidly  in  numbers.  Although  the  process  of  clotting 
consists  therefore  in  the  conversion  of  a  hydrosol  into  a  hydrogel  (see 
page  GO),  it  is  a  unique  process;  a  solution  of  the  blood  protein  which 
is  responsible  for  the  formation  of  the  fibrin  (fibrinogen)  may,  like  other 
colloidal  solutions,  be  precipitated  in  a  variety  of  ways,  but  it  is  only 
when  the  conditions  are  favorable  for  blood  clotting  that  fibrin  needles, 
and  therefore  fibrin  threads,  are  formed.  The  blood  of  invertebrates 
forms  a  structureless  gel  when  it  clots  (Howell). 

Methods  of  Retarding-  Clotting  of  Drawn  Blood 

To  understand  the  nature  of  the  clotting  process  and  the  factors  that 
are  responsible  for  its  occurrence,  it  is  advantageous  to  simplify  the 
conditions  somewhat  by  getting  rid  of  the  red  corpuscles  and  most  of 
the  other  formed  elements  of  the  blood  and  then  using  the  fluid  in 
which  these  are  suspended  in  living  blood — namely,  the  plasma.  This 
separation  of  blood  into  corpuscles  and  plasma  is  readily  effected  either 
by  sedimentation  or  by  centrifuging  after  measures  have  been  taken  to 
inhibit  or  greatly  delay  the  clotting  process.  The  methods  used  for  this 
purpose  are  numerous.  A  few  of  the  most  important  are  as  follows: 
(1)  Keeping  the  blood  at  a  temperature  very  slightly  above  freezing 
point.  This  method  is,  however,  not  very  effective  unless  the  blood  is 
immediately  received  into  narrow  vessels  placed  in  ice  and  the  tempera- 
ture kept  most  strictly  at  the  low  level.  In  the  case  of  horses'  blood  and 
other  slowly  clotting  bloods,  the  method  succeeds  without  these  precau- 
tions. (2)  Receiving  the  blood  through  a  strictly  clean  and  smooth  can- 
nula, coated  with  a  layer  of  paraffin  or  vaseline,  into  a  vessel  similarly 
coated.     This  method  is  of  practical  importance  when  it  is  necessary  to 


100  THE   BLOOD   AND    THE   LYMPH 

transfuse  blood  without  making  a  vessel-to-vessel  anastomosis.  (3)  Mix- 
ing the  blood  with  chemicals  that  are  capable  of  removing  the  calcium 
from  solution.  Such  reagents  are  potassium  or  sodium  oxalate  (in  a  con- 
centration of  0.1  per  cent  after  mixing),  and  sodium  fluoride  and  sodium 
citrate  (2  per  cent  solution,  with  one  part  of  the  solution  to  four  parts 
of  blood).  (4)  Mixing  the  blood  with  certain  neutral  salts,  particularly 
the  sulphates  of  sodium  and  magnesium  (one  part  of  27  per  cent  solution 
of  magnesium  sulphate  mixed  with  four  parts  of  blood).  Blood  thus 
treated  is  known  as  "salted  blood,"  and  the  plasma  separated  by  centri- 
fuging,  as  "salted  plasma."  Clotting  is  readily  induced  by  adding  water 
to  the  salted  blood  or  plasma,  and  in  this  way  diminishing  the  concen- 
tration of  the  salts.  (5)  The  addition  to  blood  of  one  of  a  class  of  sub- 
stances known  as  antithrombins.  Leech  extract  or  the  purified  substance 
separated  from  it,  known  under  the  trade  name  of  "hirudin,"  and  sub- 
stances present  in  blood  removed  from  animals  after  they  have  been 
injected  with  peptone  solutions,  are  examples. 

The  methods  which  have  just  been  described  are  those  applied  to  blood 
after  it  has  left  the  blood  vessels.  Another  interesting  group  of  anti- 
coagulants prevent  clotting  only  when  injected  into  the  blood  vessels  of 
the  living  animal.  The  most  powerful  example  of  this  group  is  snake 
venom,  certain  varieties  of  which  can  prevent  clotting  in  the  dosage  of 
Y10q  of  a  milligram  for  each  kilogram  of  body  weight.  Similar  but  much 
less  potent  effects  are  produced  by  the  injection  of  several  proteolytic 
enzymes,  but  most  attention  has  been  paid  to  the  effect  of  commercial 
peptone  injected  in  solution  intravenously  in  the  proportion  of  0.3  gram 
to  each  kilogram  of  body  weight.  Blood  subsequently  removed  up  to  about 
half  an  hour  or  more  does  not  clot,  and  as  we  have  already  seen,  if  added 
to  blood  from  another  animal,  materially  retards  clotting.  This  group  of 
intra  vitam  anticoagulants  is  particularly  interesting,  since  none  of  the 
substances  belonging  to  it  is  capable  of  preventing  clotting  of  blood 
when  mixed  with  this  after  it  has  been  shed.  Their  action  therefore 
obviously  depends  on  the  production  of  some  substance  in  the  body, 
probably,  as  we  shall  see  later,  in  the  liver,  since  they  fail  to  act  after 
the  removal  of  this  organ  from  the  circulation  (see  page  111). 

The  time  of  clotting  varies  greatly  according  to  the  conditions  under 
which  the  blood  is  collected  and  the  animal  from  which  it  is  derived. 
Human  blood,  for  example,  received  into  a  test  tube  from  a  puncture 
through  the  skin  may  clot  at  any  time  within  three  or  ten  minutes,  five 
minutes  being  taken  as  an  average  time  for  blood  kept  at  a  temperature 
of  about  20°  C.  This  time  may  be  considerably  shortened  by  increasing 
the  extent  of  foreign  material  with  which  the  blood  comes  into  contact, 
and  more  particularly  by  whipping  the  blood  with  a  bunch  of  twigs  or 


BLOOD    CLOTTING  -101 

wires.  In  this  Latter  case,  however,  the  clot  docs  mil  Eorm  in  the  usual 
manner,  but  the  line  threads  of  fibrin  collect  on  the  twigs  or  wires,  leav- 
ing behind  the  blood  serum  with  the  corpuscles  still  suspended  in  it. 
The  fibrin  removed  in  this  way  may  then  be  washed  free  of  adherent 
scrum.  The  serum  and  corpuscles  now  Form  dcfibriiKitrd  blood,  which 
is  used  for  many  physiologic  purposes.  Clotting  is  also  greatly  acceler- 
ated by  allowing  the  blood  to  flow  over  exposed  tissues.  Something  is 
evidently  added  to  it  from  the  tissues  which  accelerates  the  clotting 
process,  this  influence  being  particularly  marked  in  the  case  of  blood 
of  the  lower  vertebrates.  When  the  blood  of  the  bird,  for  example,  is 
received  through  a  cannula  inserted  directly  into  a  vessel  with  as  little 
injury  to  the  Avails  as  possible,  it  very  slowly  clots  if  at  all,  but  soon 
does  so  if  the  blood  is  allowed  to  come  into  contact  with  excoriated 
tissues,  or  if  it  is  mixed  with  tissue  extract,  such  as  that  of  muscle. 
Clotting  is  considerably  accelerated  by  warming  the  blood.  The  ap- 
plication of  a  cloth  or  tampon  well  wrung  out  with  hot  physiological 
saline  to  a  wounded  surface  is  a  most  efficient  means  of  allaying  hem- 
orrhage from  vessels  too  small  to  ligate. 

The  Nature  of  the  Clotting  Process 

Plasma  obtained  by  centrifuging  blood  that  has  been  prevented  from 
clotting  by  one  of  the  foregoing  methods  can  be  made  to  clot  by  removing 
the  inhibiting  influence;  for  example,  in  cooled  plasma  by  warming  the 
blood  to  room  temperature,  in  salted  plasma  by  diluting  it  with  at  least 
an  equal  volume  of  water,  and  in  decalcified  plasma  by  adding  a  suffi- 
cient amount  of  soluble  calcium  salts  to  combine  with  all  the  added 
oxalate  and  leave  a  small  trace  of  calcium  salts  in  excess. 

The  first  question  concerns  the  source  of  the  fibrin,  and  the  answer  to 
it  is  furnished  by  comparing  the  composition  of  bood  plasma  with  that 
of  serum.  Though  both  of  these  fluids  contain  the  proteins,  albumin 
and  globulin,  in  approximately  the  same  concentrations,  the  plasma  also 
contains  another  protein  not  unlike  globulin  in  most  of  its  reactions, 
but  distinguished  from  typical  globulin  in  that  it  is  precipitated  by 
half-saturation  with  sodium  chloride,  in  which  typical  globulin  is  solu- 
ble, and  is  more  readily  coagulated  by  heat.  To  produce  half -saturation 
of  the  plasma  with  sodium  chloride,  equal  volumes  of  plasma  and  satu- 
rated sodium-chloride  solution  are  mixed  together.  The  precipitate  of 
fibrinogen,  as  the  substance  is  called,  is  then  collected  at  the  bottom  of 
the  tube  by  centrifuging  and  is  washed  several  times  by  decantation  with 
half-saturated  sodium-chloride  solution.  The  washed  precipitate,  dis- 
solved in  weak  saline  solution  (preferably  containing  a  trace  of  bicar- 
bonate), will  then  be  found  to  clot  under  certain  conditions. 


102  THE   BLOOD   AND   THE   LYMPH 

The  next  question  concerns  the  nature  of  the  conditions  that  cause  the 
fibrinogen  to  clot.  When  a  fibrinogen  solution  is  mixed  with  a  few  drops 
of  blood  serum,  a  clot  usually  forms,  which  however  is  not  the  case  when 
plasma  is  added  or  when  the  serum  is  heated  before  adding  it.  Because 
a  small  quantity  of  serum  is  capable  of  causing  the  clotting  of  a  large 
quantity  of  fibrinogen  solution  or  plasma,  it  is  supposed  that  the  active 
substance  present  in  it  is  of  the  nature  of  a  ferment — fibrin  ferment  or 
thrombin.  It  must  be  pointed  out,  however,  that  there  is  considerable 
doubt  whether  this  active  body  is  really  of  the  nature  of  a  ferment  or 
enzyme.  For  example,  although  heated  serum  does  not  cause  clotting, 
thrombin,  prepared  from  serum  by  the  method  about  to  be  described,  in 
the  absence  of  inorganic  salts  can  withstand  even  a  boiling  temperature. 
Moreover,  true  enzymes  are  characterized  by  the  fact  that,  like  other 
catalytic  agents,  a  very  minute  quantity  can  effect  a  change  in  an  indef- 
inite amount  of  substance  without  the  enzyme  becoming  used  up  in  the 
process  (page  72).  When  thrombin  is  allowed  to  act  upon  a  fibrinogen 
solution,  on  the  other  hand,  it  is  said  that  only  a  fixed  amount  of  fibrin 
can  be  formed  when  a  small  amount  of  thrombin  is  added.  Neither  does 
this  amount  increase  when  the  time  of  reaction  is  prolonged. 

Whatever  may  be  the  significance  of  the  foregoing  facts,  it  is  impor- 
tant to  know  that  the  clotting  substance,  thrombin,  can  be  isolated  from 
blood  serum  in  a  tolerably  pure  condition.  For  this  purpose  blood 
serum  is  allowed  to  stand  under  a  large  volume  of  alcohol  for  a  week  or 
two ;  the  precipitate  is  then  collected  and  rubbed  up  with  water,  which 
extracts  the  thrombin  from  it,  leaving  the  serum  protein  in  a  coagulated 
state.  The  resulting  watery  solution  of  thrombin  may  be  further  pre- 
cipitated by  alcohol,  the  precipitate  washed  in  alcohol  and  redissolved 
in  water,  yielding  ultimately  a  solution  which  exhibits  very  marked  co- 
agulating powers  when  added  to  plasma  or  fibrinogen  solution.  Throm- 
bin shows  most  of  the  protein  reactions  but  it  is  not  coagulated  by  heat. 
As  would  be  expected,  a  considerable  quantity  of  thrombin  remains 
adherent  to  the  fibrin  formed  in  the  process  of  clotting,  and  Howell8 
describes  a  very  Useful  method  by  which  it  can  be  separated  from  fibrin 
and  preserved  in  a  dry  condition.  Briefly  stated,  this  method  consists, 
in  allowing  washed  fibrin  to  stand  overnight  under  eight  per  cent 
sodium-chloride  solution,  which  dissolves  the  thrombin.  The  resulting 
extract  is  then  mixed  with  an  equal  volume  of  acetone,  which  throws 
down  a  precipitate  containing  the  thrombin.  To  preserve  it,  the  precip- 
itate is  collected  on  a  number  of  small  filter  papers,  which  are  subse- 
quently opened  out  and  dried  by  exposure  to  a  current  of  cold  air  before 
an  electric  fan.  When  the  thrombin  solutions  are  desired,  the  dried  pre- 
cipitates are  extracted  with  a  little  water. 


BLOOD    CLOTTING  L03 

Thrombin  does  not  exist  in  blood  plasma,  for  if  ;i  clean  and  paraffined 
glass  tube  is  inserted  into  an  artery  and  the  blood  collected  under  al- 
cohol, the  precipitate  after  standing  a  few  weeks  will  yield  no  thrombin 
when  triturated  with  Mater.  Quite  clearly,  therefore,  the  thrombin  is 
produced  at  the  time  the  blood  clots,  and  the  question  arises,  "What  is 
it  produced  from?  It  will  be  remembered  that,  when  the  blood  is  ex- 
amined under  the  microscope  during  the  clotting  proecss,  the  fibrin 
threads  are  seen  to  start  from  foci  which  correspond  to  the  blood  plate- 
lets. It  would  appear  therefore  that  the  thrombin  must  be  derived  from 
some  substance  that  is  shed  forth  from  the  platelets  during  the  disin- 
tegration which  they  undergo  shortly  after  the  blood  is  shed.  The  sub- 
stance is  called  prothrombin.  The  platelets  or  their  precursors,  the 
megacaryocytes  of  red  bone  marrow,  are  probably  not  its  only  source, 
for  clotting  may  occur  in  the  complete  absence  of  platelets,  when  it 
appears  to  come  from  the  leucocytes.  Prothrombin  appears  plentifully 
in  the  fluid  used  to  perfuse  red  bone  marrow  outside  the  body  (Drinker 
and  Drinker9). 

To  sum  up  what  we  have  so  far  learned,  it  may  be  stated  that  the 
process  of  clotting  starts  with  the  disintegration  of  blood  platelets  and 
probably  of  leucocytes,  as  a  result  of  which  there  is  shed  forth  into  the 
plasma  a  substance  called  prothrombin,  which  immediately  afterward 
becomes  activated  or  converted  into  thrombin.  The  thrombin  then  at- 
tacks a  protein  present  in  plasma  called  fibrinogen,  producing  from  it  in 
thread-like  form  the  insoluble  protein,  fibrin.  But  this  does  not  com- 
plete the  history,  for  at  least  two  other  important  factors  come  into 
play;  the  one  is  the  presence  of  soluble  calcium  salts,  and  the  other  that 
of  peculiar  substances  derived  from  the  tissues  outside  the  blood  vessels 
and  called  thromboplastic  substances  or  thromboplastin  (Howell).  We 
must  now  consider  the  action  of  these  two  factors. 

The  Influence  of  Calcium  Salts. — As  already  explained,  the  proof  that 
soluble  calcium  salts  are  necessary  for  clotting  is  furnished  by  the  ob- 
servation that  the  process  is  entirely  prevented  when  the  freshly  drawn 
blood  is  mixed  with  soluble  oxalate.  To  this  proof,  however,  objection 
might  be  made  on  the  score  that  the  oxalate  per  se  inhibited  the  clotting. 
That  such  is  not  the  case  is  indicated  by  the  fact  that,  if  the  oxalated 
blood  or  plasma  is  dialyzed  against  physiologic  saline  solution  till  all 
the  soluble  oxalate  has  been  removed  from  it,  clotting  is  still  absent  but 
immediately  supervenes  if  some  soluble  calcium  salts  are  added.  The 
question  arises  as  to  how  the  calcium  ion  acts.     Two  possibilities  exist: 

(1)  that  it  is  concerned  in  the  conversion  of  fibrinogen  to  fibrin,  and 

(2)  that  it  is  necessary  for  converting  prothrombin  into  thrombin.     It 
can  quite  readily  be  shown  that  it  is  by  the  second  of  these  processes 


104  THE    BLOOD    AND    THE   LYMPH 

that  the  calcium  acts;  for  example,  clotting  occurs  when  purified  throm- 
bin is  added  to  dialyzed  oxalate  blood  or  plasma  or  to  a  pure  solution  of 
fibrinogen.  Citrates  prevent  clotting  by  forming  calcium  citrate,  which 
although  soluble  does  not  ionize  in  solution.  It  is  the  free  calcium  ions 
that  are  important.  The  action  of  the  fluoride  is  somewhat  mysterious, 
for  it  has  been  found  that  to  produce  clotting  in  fluoride  plasma  the  sim- 
ple addition  of  calcium  chloride  will  not  suffice;  thrombin  itself  must  be 
added  as  well.  Some  authors  assert,  however,  that  if  the  calcium  chlo- 
ride is  added  cautiously  to  "fluoride"  blood,  it  will  induce  clotting 
(Rettger).  In  any  case  it  appears  that  the  fluoride  does  something  more 
than  precipitate  the  calcium;  possibly  it  prevents  the  breaking  up  of 
platelets  and  leucocytes. 

The  Influence  of  the  Tissues. — As  already  stated,  when  slowly  clotting 
blood,  like  that  of  a  bird,  is  collected  through  a  sterile  glass  tube  into  a 
thoroughly  clean  vessel  and  immediately  centrifuged,  the  plasma  will 
often  remain  indefinitely  unclotted.  If  an  extract  of  some  tissue,  such 
as  muscle,  is  added,  however,  the  plasma  immediately  clots.  To  a  much 
less  degree,  the  same  phenomenon  is  exhibited  by  mammalian  plasma 
when  it  is  collected  in  a  similar  manner.  From  these  observations  the 
conclusions  may  be  drawn  that  the  tissues  furnish  some  substance  as- 
sisting in  the  clotting  process,  and  that  this  substance  is  also  formed 
from  certain  elements  present  in  mammalian  but  not  present  in  avian 
blood.  The  absence  of  platelets  from  the  latter  blood  suggests  that 
these  must  be  the  source  of  the  activating  substance  in  mammalian  blood. 
It  is  plain  that  this  tissue  factor  in  clotting  is  of  importance  in  hasten- 
ing the  process  when  an  animal  is  wounded. 

Before  attempting  to  formulate  an  hypothesis  that  will  explain  the 
process  of  clotting,  it  is  necessary  to  call  attention  to  one  other  impor- 
tant fact.  This  refers  to  the  presence  in  blood  of  a  substance  that  pre- 
vents clotting  and  is  hence  called  antithrombin.  Antithrombin  is  pres- 
ent in  normal  blood,  for  a  given  specimen  of  pure  fibrinogen  will  clot 
less  rapidly  when  mixed  with  serum  to  which  some  oxalated  plasma  has 
been  added  than  with  an  equal  amount  of  the  same  serum  correspond- 
ingly diluted  with  a  solution  of  soluble  oxalate.  A  striking  increase 
in  the  concentration  of  antithrombin  in  blood  can  be  brought  about  by 
rapidly  injecting  a  solution  of  commercial  peptone  into  the  blood  ves- 
sels fifteen  to  thirty  minutes  before  bleeding.  The  peptonized  blood  or 
plasma  will  remain  fluid  for  many  hours,  if  not  indefinitely.  That  the 
failure  of  this  blood  to  clot  depends  on  the  presence  of  some  anticlotting 
substance,  and  not  upon  the  absence  of  one  of  the  necessary  clotting  sub- 
stances (fibrinogen,  thrombin,  etc.),  is  evidenced  by  the  fact  that  the 
addition  of  .some  of  it  to  a  mixture  of  thrombin  and  fibrinogen  inhibits 


BLOOD   CLOTTING  105 

the  coagulation,  which  it  docs  not  do,  however,  it'  it  is  first  of  all  heated 
to  80°  0.  and  filtered  free  of  the  coagulated  protein.  Moreover,  the 
antagonistic  action  is  quantitative  in  the  sense  that  a  fixed  amount  of 
the  peptone-plasma  inhibits  the  action  of  a  fixed  amount  of  thrombin. 
The  source  of  antithrombiu  in  the  body  appears  to  be  mainly  at  Least 
the  liver,  for  it  has  been  found:  (1)  that  peptone  injection  into  an  animal 
from  which  the  liver  has  been  removed  does  not  cause  antithrombiu  to 
be  formed  (Denney  and  Minot)  ;10  (2)  that  peptone  injections  into  the 
portal  vein  cause  antithrombin  to  appear  in  the  blood  much  more  rap- 
idly than  when  the  injection  is  made  into  a  systemic  vessel ;  and  (3)  that, 
when  the  liver  is  perfused  outside  the  body  with  a  perfusion  fluid  con- 
taining peptone,  antithrombin  accumulates  in  the  perfusion  fluid. 
'  A  fluid  containing  a  high  concentration  of  antithrombin  is  secreted 
by  the  so-called  salivary  gland  at  the  head  end  of  the  leech.  The  func- 
tion of  the  fluid  is  to  prevent  clotting  of  the  blood,  so  that  the  animal 
may  continue  to  suck  it  without  interference  by  clotting.  After  apply- 
ing leeches  for  medicinal  purposes  it  is  therefore  necessary  to  wash  the 
wound  thoroughly  with  water  so  that  all  traces  of  the  antithrombin  may 
be  removed ;  otherwise  the  bleeding  may  continue  for  a  considerable  time. 
Practical  use  is  made  of  this  effect  of  the  leech  to  prevent  clotting  of  blood 
outside  the  body,  or  it  may  be  used  to  inhibit  coagulation  intra  vitam  in 
experiments  where  clotting  would  otherwise  interfere  with  their  prog- 
ress; for  example,  in  crossed  circulation  experiments  (page  365)  and  in 
experiments  in  vividiffusion  (page  607).  For  such  purposes  the  leech 
head  is  cut  off  and  extracted  either  with  saline  or  by  treatment  with 
chloroform,  which  removes  other  proteins  from  the  saline  solution  leav- 
ing a  strong  antithrombin,  known  under  the  trade  name  of  "hirudin." 
At  temperatures  about  that  of  the  body  the  action  of  antithrombin  is 
greatly  augmented.  In  animals  like  the  mammals  in  which  the  content 
of  antithrombin  is  small,  this  may  be  important  in  maintaining  the  flu- 
idity of  the  blood  (Howell).  Blood  containing  antithrombin  can  be 
made  to  clot  by  the  addition  of  thrombin,  and  therefore  of  blood  serum. 


CHAPTER  XIII 
BLOOD:  BLOOD  CLOTTING  (Cont'd) 

THEORIES  OF  BLOOD  CLOTTING 

Attempts  to  link  all  the  foregoing  facts  together  in  the  form  of  a 
simple  theory  have  not  so  far  been  entirely  successful.  All  agree  that 
the  fibrin  is  derived  from  fibrinogen  by  the  action  of  thrombin,  the  points 
in  dispute  being  those  which  concern  the  origin  of  the  thrombin  and 
the  mode  of  action  of  the  calcium  and  thromboplastic  substances.  The 
theory  most  widely  accepted  in  Europe  is  that  of  Morawitz,  according 
to  which  the  thrombin  exists  in  living  blood  in  an  inactive  state  called 
thrombogen  (prothrombin),  which  becomes  converted  into  thrombin  by 
the  simultaneous  action  on  it  of  soluble  calcium  salts  and  of  thrombo- 
plastic substances  furnished  by  the  tissue  cells  in  general  and  by  the 
cellular  elements  of  the  blood  platelets  and  leucocytes.  According  to 
this  view  the  thromboplastic  substance,  aided  by  the  presence  of  calcium 
ions,  converts  thrombogen  (prothrombin)  to  thrombin.  It  acts  there- 
fore as  a  kinase  and  is  called  thrombokinase.  The  fundamental  fact  of 
this  theory,  then,  is  that  kinase  is  necessary  for  the  union  of  the  cal- 
cium with  prothrombin — a  fact,  however,  which  is  challenged  by  Howell, 
who  states  that  prothrombin  may  be  converted  to  thrombin  by  the  action 
of  calcium  ions  alone.  This  investigator  believes  that  the  thrombo- 
plastic substance  acts  not  as  a  kinase  but  because  it  neutralizes  anti- 
thrombin,  which  is  constantly  present  in  the  blood,  and  the  function  of 
which  is  to  prevent  the  calcium  from  uniting  with  the  prothrombin  to 
form  thrombin.  Howell's  theory  in  his  own  words  is  as  follows:  "In 
the  circulating  blood  we  find  as  constant  constituents  fibrinogen,  pro- 
thrombin, calcium  salts  and  antithrombin.  The  last  named  substance 
holds  the  prothrombin  in  combination  and  thus  prevents  its  conversion 
or  activation  to  thrombin.  When  the  blood  is  shed,  the  disintegration 
of  the  corpuscles  (platelets)  furnishes  material  (thromboplastin)  which 
combines  with  the  antithrombin  and"  at  the  same  time  liberates  more 
"prothrombin;  the  latter  is  then  activated  by  the  calcium  and  acts  on 
the  fibrinogen."  Antithrombin  can  also  prevent  the  action  of  thrombin 
on  fibrinogen.  As  already  pointed  out,  the  thromboplastin  can  be  de- 
rived from  the  blood  itself  in  the  mammals,  but  only  from  the  tissues 
in  the  lower  vertebrates.    It  is  interesting  to  note  that  the  thromboplastin 

190 


BLOOD   CLOTTING  107 

can  be  extracted  from  the  (issues  by  Cat-solvents,  and  thai  il  appears  to 
belong  to  the  class  of  phosphatids,  being  indeed  closely  related  to,  if 

not   identical  with,  kephalin  (Howell). 

Intravascular  Clotting- 

The  practical  application  of  the  theory  of  blood  clotting  concerns  the 
manner  in  which  the  blood  is  maintained  in  a  fluid  condition  in  the  blood 
vessels,  and  the  disturbance  of  this  function  causing  intravascular  clot- 
tint/.  According  to  the  one  theory,  the  hlood  is  maintained  fluid  by  the 
absence  from  it  of  any  considerable  quantity  of  kinase,  and  according 
to  the  other,  by  the  presence  in  it  of  an  amount  of  antithrombin  suffi- 
cient to  prevent  the  union  of  calcium  with  prothrombin.  The  fluidity 
is  maintained  even  when  large  amounts  of  thrombin  or  of  blood  serum, 
which  contains  this  substance,  are  injected  into  the  living  animal.  We 
can  best  explain  the  immunity  of  the  blood  to  the  action  of  thrombin  un- 
der these  circumstances  as  being  due  to  the  instantaneous  appearance  in  it 
of  antithrombin  in  amounts  sufficient  to  prevent  the  action  of  thrombin 
on  fibrinogen,  for,  as  stated  above,  it  is  claimed  by  Howell  that  anti- 
thrombin has  this  influence  as  well  as  that  of  preventing  the  conversion 
of  prothrombin  into  thrombin. 

Intravascular  clotting  may  be  brought  about  by  a  variety  of  means: 
(1)  Mechanical  damage  to  the  lining  of  the  blood  vessels;  after  the  ap- 
plication of  a  ligature,  for  example,  the  damaged  endothelium  is  soon 
covered  by  a  clot,  which  gradually  becomes  firmer  and  firmer,  and  may 
spread  up  the  vessel  to  the  next  branch.  (2)  The  presence  of  foreign 
substances  in  the  blood.  Emboli,  for  example,  are  apt  to  cause  clots 
to  form  at  the  places  where  they  stick,  namely,  in  the  smaller  vessels. 
Clotting  is  also  a  frequent  occurrence  when  there  are  local  dilatations  of 
the  cardiovascular  tube,  and  it  may  occur  under  imperfectly  understood 
conditions  causing  the  condition  known  as  tlirombosis.  (3)  An  inter- 
esting variety  of  intravascular  clotting  is  that  caused  by  the  intrave- 
nous injection  of  saline  extracts  of  cell-rich  tissues,  such  as  the  thymus, 
lymph  glands  or  testes  (Wooldridge).  By  precipitation  with  acetic 
acid  and  digestion  with  peptone,  a  residue  can  be  obtained  from  these 
extracts  which,  when  dissolved  in  alkali,  has  a  very  pronounced  intra- 
vascular clotting  effect.  Since  these  precipitates  are  very  rich  in  phos- 
phorus, it  is  probable  that  they  are  of  the  nature  of  phosphoprotein 
(nucleoalbumin) .  Their  action  must  depend  on  neutralization  of  anti- 
thrombin, according  to  Howell's  theory,  or  because  they  serve  as  throm- 
bokinases  (according  to  Morawitz'  theory). 

As  a  matter  of  fact,  however,  the  foregoing  observation  is  not  com- 
pletely explained  by  either  theory.     If  in  place  of  making  one  injection 


108  THE   BLOOD    AND    THE    LYMPH 

frequent  injections  of  small  amounts  of  the  above  material  are  made, 
instead  of  intravascular  clotting,  a  delay  in  the  coagulation  time  is 
likely  to  occur.  Indeed,  repeated  injections  of  small  amounts  may  en- 
tirely remove  the  clotting  power  of  the  blood.  The  readiness  with  which 
this  so-called  "negative  phase"  appears,  seems  to  depend  on  the  nutri- 
tive condition  of  the  animal  at  the  time  of  injection.  If  a  large  dose  is 
injected  into  a  fasting  dog,  for  example,  thrombosis  is  confined  to  the 
portal  area,  whereas  if  it  is  injected  into  a  recently  fed  animal,  the 
thrombosis  is  universal  throughout  the  vascular  system.  The  develop- 
ment of  the  negative  phase  is  undoubtedly  dependent  upon  some  reac- 
tion on  the  part  of  the  living  cells  of  the  organism,  since  it  does  not  occur 
on  the  addition  of  similar  substances  to  blood  outside  the  body.  The 
reaction  is,  indeed,  akin  to  that  by  which  immune  bodies  in  general  are 
produced.  For  example,  a  toxin  injected  in  large  amount  has  a  cer- 
tain toxic  effect,  but  in  repeated  small  doses  with  intervening  intervals 
it  leads  to  the  production  of  an  antitoxin.  So  with  the  substance  in 
question;  a  large  dose  injected  at  one  time  causes  a  positive  effect — clot- 
ting— but  smaller  doses  frequently  injected,  the  opposite  effect — want  of 
clotting.  It  is  probable,  as  suggested  by  Starling,  that  more  intensive 
study  of  the  conditions  causing  intravascular  clotting  will  throw  con- 
siderable light  on  the  general  question  of  the  production  of  immunity. 

Measurement  of  the  Clotting  Time 

To  measure  the  clotting  time  of  drawn  samples  of  Mood,  several  con- 
ditions must  be  observed.  These  have  been  tabulated  by  Addis11  as 
follows: 

1.  The  specimens  of  blood  must  always  be  obtained  by  exactly  the 
same  technic.  It  would  introduce  serious  errors  to  compare  the  clot- 
ting time  of  one  specimen  of  blood  received  from  an  incision  of  the 
skin  (ear  lobe)  with  that  of  another  collected  in  a  syringe  by  veni- 
puncture. 

2.  The  temperature  conditions  must  always  be  the  same.  Probably 
25°  C.  is  the  best  temperature  to  use.  Higher  temperatures  are  unsuit- 
able for  two  reasons:  first,  because  during  its  collection  the  blood  will 
have  become  cooled  to  about  or  below  this  point,  and  time  would  be  con- 
sumed in  raising  it  higher;  and  second,  because  the  time  of  coagulation 
is  more  and  more  shortened  for  each  degree  that  the  temperature  is 
raised,  this  acceleration  becoming  especially  pronounced  for  tempera- 
tures above  25°  C.  Quite  apart  from  the  liability  to  incur  errors  inci- 
dent to  measurement  of  shorter  periods  of  time,  observations  at  higher 
temperatures  necessitate  most  rigorous  adherence  to  a  fixed  temperature 
of  the  water-bath.    Temperatures  much  below  25°  C.  are  unsuitable,  be- 


|:l.(t(i|)    ri.oTTINC 


109 


cause  the  clotting  sols  in  gradually  and  it   is  difficult  to  tell  precisely 
when  it  occurs. 

3.  The  blood  must  always  be  collected  in  the  same  sort  of  vessel  and 
conic  in  contact  with  the  same  kind  and  amount  of  foreign  material. 
To  this  it  may  be  added  that  the  receiving  vessel  must  be  scrupulously 
clean;  any  trace  of  old  blood  clot  or  of  serum  is  especially  to  be  guarded 
against. 

4.  The  end  point  must  be  sharp.  It  is  here  that  the  greatest  technical 
difficulties  are  met  with  in  making  precise  measurements,  and  it  is 
greatly  to  be  desired  that  different  investigators  should  adopt  some  uni- 
form method.  For  experimental  purposes  the  method  of  Cannon  and 
Mendenhall12  is  no  doubt  the  best,  and  it  has  the  added  advantage  of 
giving  a  graphic  record  of  the  observations.  The  accompanying  figure 
(Fig.  19)  shows  the  principle  of  the  method.  The  blood  is  received 
through  a  standard  cannula  (C)  into  a  tube  (T)  5  cm.  long  and  of  5  mm. 


F 

-h 

"*~ *        v 

D 

:    1 

R*                                         * 

Fig.  19. — Diagram  of  the  graphic  coagulometer.  The  cannula  at  the  right  rested  in  a  water 
bath  not  shown  in  this  diagram.  For  further  description  see  text.  (From  Cannon  and  Men- 
denhall.)* 

internal  diameter;  and  a  loop  (of  2  mm.  diameter)  at  the  end  of  a 
copper  wire  (Z>),  which  is  8  cm.  long  and  0.6  mm.  in  diameter,  is  al- 
lowed to  fall  gently  into  the  blood  at  regular  intervals.  The  upper  end 
of  the  wire  is  articulated  with  the  short  arm  of  a  light  lever  so  counter- 
poised that  when  the  stop  (R),  which  ordinarily  holds  it  in  a  horizontal 
position,  is  released,  the  wire,  now  having  a  net  weight  of  30  nig.,  falls 
on  the  blood  in  the  tube.  The  long  arm  of  the  lever  is  provided  with 
a  writing  point,  which  is  made  to  inscribe  its  movements  on  a  drum. 
So  long  as  the  blood  is  unclotted  the  loop  sinks  into  it  when  the  lever 
is  released  and  a  vertical  line  is  traced,  but  whenever  clotting  occurs 
the  loop  sticks  on  the  blood  and  the  writing  point  does  not  rise. 

For  clinical  purposes  where  blood  collected  in  a  syringe  by  venipuncture 
is  used,  the  method  of  Howell13  is  most  accurate.     It  consists  in  placing 


'Am.    Jour.    Physiol.,    May    1,    1914,    xxxiv,    No.    2. 


110  THE   BLOOD   AND   THE   LYMPH 

2  or  4  e.e.  of  the  blood  in  a  wide  tube  (of  21  mm.  diameter)  that  has 
been  cleaned  by  a  bichromate-acid  mixture.  The  period  that  elapses 
between  the  moment  of  the  entry  of  fluid  into  the  syringe  and  that  at 
which  the  clot  has  become  firm  enough  so  that  the  tube  can  be  inverted 
without  spilling  any  blood,  is  taken  as  the  clotting  time.  Since  the  blood 
does  not  come  in  contact  with  exposed  tissues,  it  takes  from  20  to  60 
minutes  to  clot  by  this  method. 

For  routine  clinical  examination  of  blood  taken  from  a  skin  wound 
Brodie  and  Russel's  method14  is  most  satisfactory.  This  consists  in 
principle  in  observing  a  drop  of  blood,  under  the  low  power  of  the 
microscope,  while  a  fine  current  of  air  is  gently  blown  against  it  at 
regular  intervals  in  a  tangential  direction.  Until  clotting  sets  in,  the 
individual  corpuscles  move  freely  in  a  circular  direction,  but  as  soon 
as  clotting  begins  they  move  in  masses  which  soon  tend  to  become  fixed 
so  that,  although  they  move  somewhat  when  the  air  impinges  on  them, 
they  immediately  return  to  their  original  position  when  the  current 
is   discontinued.      When    clotting   is    complete,    the    air    current   merely 


Fig.  20. — Coagulometer.  The  drop  of  biood  is  placed  on  the  lower  end  of  the  glass  cone  and 
the  air  stream  is  directed  against  it  from  the  side  tube  shown  by  the  black  dot.  The  apparatus 
is    placed    on    the    stage    of    the    microscope    and    the    drop    observed    by    the    low    power. 

presses  on  the  corpuscles  at  one  point,  By  this  method  the  clotting 
time  averages  five  minutes.  A  convenient  apparatus  for  this  method  is 
that  of  Boggs,  which  is  shown  in  Fig.  20.  It  consists  of  a  truncated 
cone  of  glass,  projecting  into  a  moist  chamber  provided  with  a  tube  on 
the  side  so  arranged  that  when  air  is  blown  into  the  chamber,  it  strikes 
the  drop  of  blood  placed  on  the  end  of  the  cone  tangentially. 

Blood  Clotting  in  Certain  Physiologic  Conditions 

Besides  the  experimental  conditions  already  enumerated  as  changing 
the  clotting  time  in  the  blood  of  laboratory  animals,  special  mention 
must  be  made  of  the  influence  of  epinephrine  injections,  of  conditions 
supposed  to  cause  a  hypersecretion  of  this  hormone,  of  the  emotions, 
and  of  hemorrhage. 

Epinephrine  added  to  drawn  blood  does  not  affect  the  clotting  time, 
but  if  small  amounts  are  injected  intravenously  or  even  subcutaneously, 
a  marked  decrease  occurs  (Camion  and  Gray;  cf.  Cannon,  loc.  cit.). 
Larger  injections  may  have  the  opposite  effect,  and  intermediate  amounts 


BLOOD  CLOTTING  1 1 1 

limy  cause  at  (irsl  a  prolongation  and  later  a  shortening  of  the  time. 
These  results  with  Larger  doses  arc  related  to  Howell's  observation  that 
repeated  doses  of  relatively  large  amounts  of  epinephrine  in  dogs  may 
so  greatly  retard  coagulation  as  to  make  the  animals  practically  hemo- 
philic. It  "was  further  found  by  Cannon  and  his  coworkers  that  epineph- 
rine does  not  influence  the  clotting  time  when  injected  into  animals 
from  which  the  abdominal  viscera  have  been  removed  from  the  circulation 
by  Ligation  of  the  inferior  vena  cava  and  the  abdominal  aorta.  In  the  light 
of  the  .influence  which  destruction  of  liver  cells  (by  phosphorus,  chloro- 
form, etc.)  is  known  to  have  in  lengthening  clotting  time,  it  would  seem 
reasonable  to  conclude  that  it  must  be  through  this  organ  that  epineph- 
rine develops  its  clotting  effects. 

Stimulation  of  the  splanchnic  nerves  also  shortens  the  clotting  time, 
and  it  would  appear  that  this  action  depends  on  the  resulting  hyperse- 
cretion of  epinephrine  (page  74G),  for  it  is  not  observed  following  stimula- 
tion of  the  nerves  in  animals  from  which  the  adrenal  glands  have  been 
excised  (Cannon  and  Mendenhall).  The  interesting  suggestion  is  made 
by  Cannon  that  the  shorter  clotting  time  observed  in  animals  showing 
strong  emotions  of  fright  or  fear  may  also  be  due  to  the  hypersecretion 
of  epinephrine  which  this  worker  believes  accompanies  such  states. 

Blood  Clotting-  in  Disease 

With  the  factors  concerned  in  the  process  so  wrapped  in  mystery,  it  is 
not  surprising  that  the  underlying  causes  responsible  for  delayed  or  de- 
ficient clotting  of  blood  in  diseased  conditions  or  for  the  formation  of 
intravascular  clots  (thrombi)  are  little  understood.  According  to  How- 
ell's theory  of  the  nature  of  the  process,  which  is  the  most  satisfactory  at 
the  present  time,  abnormal  clotting  might  be  due  to  the  following 
causes:  (1)  A  diminished  amount  of  fibrinogen.  This  occurs  when  the 
hepatic  cells  are  greatly  damaged,  as  in  poisoning  by  chloroform  or 
phosphorus  and  in  such  diseases  as  acute  yellow  atrophy  and  yellow 
fever.  In  many  cases  of  chronic  cirrhosis  of  the  liver,  as  Whipple,  etc.,15 
have  shown,  the  blood  also  clots  feebly  because  of  deficient  fibrinogen. 
It  should  be  pointed  out  that  it  is  not  so  much  the  clotting  time  that  is 
increased  in  such  cases,  as  the  firmness  or  consistency  of  the  clot  that 
is  affected. 

2.  A  deficiency  in  prothrombin.  In  the  condition  known  as  "melena 
neonatorum,"  undoubted  benefit  is  derived  from  intravenous  injections 
of  blood  serum  or  by  direct  blood  transfusions,  probably  because  throm- 
bin or  prothrombin  is  thus  furnished. 

3.  A  deficiency  of  thromboplastin.  Since  this  substance  is  derived  from 
both  blood  cells  and  tissue  cells,  it  does  not  seem  likely  that  a  deficiency 


112  THE   BLOOD   AND    THE   LYMPH 

could  ever  occur.    Certain  observers,  however — Morawitz,  for  example — 
lay  great  stress  on  this  as  an  important  factor  in  hemorrhagic  diseases. 

4.  An  excess  of  antithrombin.  The  undoubted  increase  in  this  substance 
that  can  be  brought  about  experimentally  by  injecting  hirudin  or  pep- 
tone into  animals,  has  stimulated  careful  search  for  a  similar  increase  in 
the  blood  in  clinical  conditions  in  which  abnormal  blood  clotting  is  one 
of  the  symptoms  (Whipple10).  Antithrombin  is  said  to  be  increased  in 
septicemia,  pneumonia,  miliary  tuberculosis,  etc. 

5.  A  deficiency  of  calcium  ions.  Although  at  one  time  it  was  supposed 
that  this  might  be  responsible  for  the  feeble  clotting  in  hemophilia,  it 
has  not  been  found,  after  very  extensive  trials,  that  the  exhibition  of 
Ca  salts  in  any  way  relieves  the  condition.  It  is  said,  however,  that  the 
slow  coagulation  seen  in  obstructive  jaundice  is  decidedly  shortened  by 
treatment  with  calcium  salts. 

One  thing  stands  out  prominently  in  connection  with  the  whole  problem, 
and  that  is  the  close  relationship  of  the  blood  platelets  to  the  clotting 
process.  From  these  cells  are  derived,  according  to  Howell,  not  only  the 
prothrombin  but  also,  as  from  other  cells,  thromboplastin.  It  is  not  sur- 
prising therefore  to  find  that  decided  alterations  in  the  platelet  count 
occur  in  cases  of  faulty  blood  clotting,  and  that  local  accumulations  of 
these  elements  within  the  blood  vessels,  produced  by  their  clumping  to- 
gether or  agglutinating,  is  followed  by  a  formation  of  local  clots,  as  in 
thrombosis. 

Hemorrhagic  Diseases 

In  many  of  the  so-called  hemorrhagic  diseases  (acute  leucemia  and 
aspastic  anemia)  and  in  the  hemorrhagic  varieties  of  diphtheria  and 
smallpox,  the  platelet  count  drops  from  its  normal  of  between  200,000 
and  800,000  per  cubic  millimeter  to  well  below  100,000,  and  indeed  in 
these  conditions  it  is  frequently  difficult  to  find  any  platelets.  Samples  of 
blood  clot  outside  the  body  within  the  normal  time,  but  the  clot  is  soft 
and  usually  fails  to  retract  in  the  normal  manner.  It  is  on  account  of 
this,  rather  than  slow  clotting  that  the  hemorrhage  continues,  so  that  in 
appraising  the  gravity  of  the  symptom  it  is  best  to  measure  not  the  clot- 
ting time  but  the  time  that  it  takes  for  bleeding  to  cease  from  a  small 
skin  wound,  as  in  the  lobe  of  the  ear.  This  can  be  very  accurately  done 
by  applying  blotting  paper  at  regular  intervals  to  the  puncture  (Duke17). 

The  most  interesting  and  at  the  same  time  the  most  mysterious  of  all 
conditions  in  which  blood  clotting  is  interfered  with  is  hemophilia.  The 
clotting  time  is  longer  than  normal,  biit  even  after  the  clot  forms,  bleed- 
ing is  likely  to  continue  because  the  clots  are  very  readily  displaced.  Both 
clotting  time  and  bleeding  time  are  increased.     So  far  no  change  in  the 


I '.Looi)   CLOTTING  113 

clotting  factors  of  the  Mood  1ms  been  demonstrated  in  lliis  disease;  the 
corpuscles  and  the  platelets  arc  normal  in  numbers,  fibrinogen  and  cal- 
cium sails  are  normal,  and,  as  Howell  has  shown,  there  is  no  excess  of 
antithrombin.  One  significant  fact,  however,  is  that  the  addition  of 
thromboplastin  or  of  its  active  ingredient,  kephalin,  greatly  shortens  the 
clotting  time  of  the  blood  when  it  is  removed  by  venipuncture.  In  agree- 
ment with  1h is  observation  it  has  been  found  that  hemophilic  blood  clots 
much  more  rapidly,  indeed  sometimes  in  the  usual  time,  if  it  is  allowed  to 
tlow  over  cut  or  damaged  tissue  and  so  become  mixed  with  thromboplas- 
tin. These  facts  taken  together  would  seem  to  indicate  that  the  fault 
must  lie  in  a  deficiency  in  prothrombin,  and  since  this  is  derived  mainly 
from  the  platelets,  which  however  are  not  decreased  in  number,  we  must 
further  assume  that  these  elements  have  undergone  some  qualitative 
change  preventing  their  disintegration.  An  accompanying  defect  in 
their  agglutinating  properties  would  at  the  same  time  explain  their  fail- 
ure in  hemophilia  to  clump  together  at  the  site  of  the  hemorrhage  so  as 
to  block  the  smaller  vessels  with  thrombi;  hence  the  prolonged  bleeding 
time  even  after  clotting  has  occurred. 

Thrombus  Formation 

The  first  formed  portion  of  a  thrombus  is  paler  than  those  formed  later, 
because  it  contains  excessive  numbers  of  platelets;  and  it  seems  clear 
that  it  is  by  agglutination  of  these  into  masses,  which  then  stick  in  the 
blood  vessels  and  by  disintegrating  shed  forth  prothrombin  and  thrombo- 
plastin, that  the  clotting  starts.  This  platelet  agglutination  may  result 
from  stagnation  in  the  bloodflow,  or  from  roughening  and  damage  to  the 
vessel  walls.  Stagnation  may  be  due  either  to  failure  of  the  circulation 
as  a  whole  as  in  heart  disease,  or  to  local  physical  alterations  in  the  vas- 
cular tube,  setting  up  conditions  in  which  eddy  currents  with  stagnant 
pools  of  blood  are  formed,  such  as  will  occur  at  places  where  the  vessels 
suddenly  become  wider,  as  in  varicose  veins,  in  aneurisms  and  at  the 
sudden  bend  of  large  veins.  The  first  formed  (platelet)  thrombus  is  fol- 
lowed by  one  of  a  darker  color,  which  fills  the  vessel  up  to  the  next 
anastomotic  branch.  Similar  stagnation  may  also  follow  the  obstruc- 
tion caused  by  lodgment  of  emboli  in  the  smaller  vessels  (air,  foreign 
bodies  in  fine  suspension,  bacteria,  etc.).  The  thrombi  in  such  cases  are 
very  small  and  occur  particularly  in  the  capillaries  of  the  liver,  spleen, 
and  lungs.  The  small  thrombi  often  serve  as  foci  from  which  clotting 
spreads  into  the  larger  vessels,  this  being  often  encouraged  by  an  increase 
in  the  coagulability  of  the  blood.  When  the  intima  is  inflamed,  it  is  pos- 
sible that  excessive  amounts  of  thromboplastin  are  produced  and  that 
this  neutralizes  the  antithrombin  in  blood  moving  so  slowly  that  it  is  not 


114  THE   BLOOD   AND   THE   LYMPH 

replaced  by  fresh  blood  before  clotting  ensues,  or  it  may  be  that  sub- 
stances derived  from  the  inflamed  tissue  cause  the  platelets  to  aggluti- 
nate. The  increased  clotting  often  observed  after  the  injection  of  hemo- 
lytic agencies  (foreign  sera,  snake  venom,  etc.)  may  also  be  due  to 
platelet  agglutination.  Like  the  thrombosis  following  embolism,  the 
clotting  occurs  at  first  in  the  capillaries,  the  initial  thrombi  containing 
masses  of  platelets  along  with  skeletons  of  blood  corpuscles  and  cells 
from  the-  blood-forming  organs. 


CHAPTEE  XIV 
LYMPH  FORMATION  AND  CIRCULATION 

GENERAL  CONSIDERATIONS 

Lymphatics  are  modified  veins.  They  grow  from  the  veins  in  embry- 
onic life  as  buds  of  endothelium,  which  are  first  visible  in  the  human 
embryo  in  the  sixth  week  of  development.  The  earliest  outgrowth  oc- 
curs from  the  internal  jugular  vein,  and  the  endothelial  buds  soon  be- 
come hollow  and  join  together,  forming  first  a  plexus  and  subsequently 
a  sac,  from  which  again  lymphatic  vessels  made  of  endothelium  grow 
out  to  invade  the  skin  of  the  head,  neck,  thorax  and  arm,  and  partly 
the  deep  structures  of  the  head.  The  sac  is  ultimately  transformed  into 
groups  of  lymph  glands.  At  a  later  stage  similar  nodes  develop  from 
certain  of  the  abdominal  veins,  forming  a  retroperitoneal  sac,  from  which 
grow  out  the  lymphatics  of  the  abdominal  and,  to  a  certain  extent,  of 
the  thoracic  viscera.  A  similar  pair  of  sacs  also  develops  from  the  iliac 
veins  supplying  the  lymphatics  for  the  skin  of  the  legs  and  abdominal 
walls.  The  retroperitoneal  and  iliac  sacs  then  become  connected  with 
the  jugular  sac  by  means  of  the  thoracic  duct.  In  the  embryo  there  are 
no  valves  in  the  lymphatic  vessels,  so  that  the  whole  system  can  be  in- 
jected either  from  the  thoracic  duct  or  from  the  skin,  showing  clearly 
that  the  superficial  and  deep  lymphatics  are  parts  of  one  closed  system 
of  vessels. 

Anatomists  have  succeeded  in  tracing  the  course  of  the  lymphatics  in 
many  parts  of  the  body.  This  knowledge  is  of  great  importance  in 
connection  with  the  spread  of  infections,  etc.  Lymphatics  are  abun- 
dant in  the  skin,  the  intestine,  and  connective  tissues,  but  are  absent 
from  the  muscle  bundles,  from  the  hepatic  lobules  (though  present  in 
the  connective  tissue  between  them),  from  the  substance  of  the  spleen, 
and  from  the  central  nervous  system. 

The  lymphatics  have  the  same  functions  as  blood  capillaries,  namely, 
to  absorb  substances  from  the  tissue  spaces.  There  is  some  evidence  to 
show  that  this  absorption  may  be  selective.  When  injections  are  made 
into  the  peritoneal  cavity,  the  pathway  of  absorption  may  be  either  the 
blood  vessels  or  the  lymphatics,  according  to  the  nature  of  the  sub- 
stance injected.    True  solutions  are  absorbed  by  the  blood,  but  granules 

135 


116  THE    BLOOD    AND    THE    LYMPH 

are  taken  up  by  special  large  cells  showing  phagocytic  powers,  and  trans- 
ferred to  the  lymphatics — for  example,  those  of  the  diaphragm.  A  sim- 
ilar selective  absorption  is  well  known  in  the  ease  of  the  villi  of  the  in- 
testine, where  fat  passes  into  the  lacteals  and  carbohydrates  into  the 
blood.  It  appears  as  if  lymphatic  adsorption,  both  of  solid  materials 
and  of  solutions,  requires  the  cooperation  of  phagocytic  cells. 

The  newer  conception  of  the  lymphatics  as  a  closed  system  is  at  vari- 
ance with  the  older  one,  in  which  they  were  supposed  to  get  smaller  and 
smaller,  and  their  walls  less  and  less  complete  until  ultimately  they 
faded  off  into  the  tissue  spaces.  These,  however,  bear  no  closer  relation- 
ship to  lymphatics  than  they  do  to  blood  capillaries.  The  tissue  spaces 
include  all  the  minute  spaces  between  the  fibers  and  cells  of  the  con- 
nective tissues  and  between  the  parenchyma  of  the  organs  and  the  great 
serous  cavities  of  the  body  (pleural,  peritoneal),  as  well  as  specially 
developed  tissue  spaces,  forming  the  subarachnoid  spaces  of  the  brain, 
the  scala  vestibuli  and  tympani  of  the  cochlea  and  the  anterior  chamber 
of  the  eye.  The  fluids  in  these  spaces — the  tissue  fluids — are  quite  dif- 
ferent from  the  lymph  in  the  lymphatics  both  in  composition  and  in 
function.  Indeed,  the  tissue  fluids  are  among  the  most  varied  of  all 
the  fluids  of  the  body.  The  spaces  may  themselves  become  linked  to- 
gether so  as  to  form  a  circulatory  system,  which  is  quite  independent  of 
the  lymphatics.  This  is  particularly  the  case  in  the  brain,  where  the  tis- 
sue spaces  surrounding  every  individual  nerve  cell  extend  into  the  sub- 
arachnoid area,  where  they  drain  into  the  cerebral  sinuses  through  the 
arachnoidal  villi,  which  exist  as  lace-like  projections  of  the  arachnoid 
into  the  dural  sinuses,  being  covered  by  a  layer  of  mesothelial  cells  spe- 
cially abundant  at  the  tips  of  the  villi,  where  they  form  cell  nests.  Ob- 
servations of  the  passage  of  substances  in  solution  by  these  pathways 
have  been  made  by  injecting  potassium  ferrocyanide  and  citrate  of  iron 
into  the  subarachnoid  and  subdural  spaces  and  afterwards  detecting 
the  presence  of  the  salts  by  mounting  sections  in  acid  media,  so  as  to 
permit  prussian  blue  to  develop.  Ordinarily  the  precipitate  is  found  in 
or  near  the  villi,  but  after  cerebral  anemia  it  forms  in  the  tissue  spaces 
that  surround  the  nerve  cells. 

There  are  therefore  three  fluids  concerned  in  the  transference  of  food 
materials  and  gases  between  the  gastrointestinal  apparatus  and  lungs 
and  the  tissue  cells — namely,  the  blood  plasma,  the  tissue  fluids,  and  the 
lymph.  The  tissue  fluid,  being  in  contact  with  the  tissue  elements,  serves 
as  their  immediate  nutritive  fluid,  and  it  is  the  function  of  the  blood  and 
lymph  to  maintain  it  of  proper  composition.  Everything  must  be  trans- 
ferred to  and  from  the  tissue  cells  through  the  tissue  fluid,  making  it 


LYMPB    FORMATION    AND   CIRCULATION  117 

therefore  in  many  ways  the  mosl  Lmportanl     of  the  Quids  of  the  body. 
In  the  tissue  cells  themselves  there  is  also  the  fluid  iii  which  the  various 

colloids  and  crystalloids  thai  cuter  into  the  composition  of  protoplasm 
arc  dissolved.  This  can  be  removed  from  cells  only  by  mechanical  means, 
such  as  grinding  with  fine  sand  in  a  mortar  ami  subjecting  the  noiss 
to  a  pressure  of  several  thousand  atmospheres  in  a  hydraulic  (Buchner) 
press.  This  is  known  as  the  tissue  juice.  The  ultimate  exchange  of 
foodstuffs  occurs  between  the  tissue  fluids  and  the  tissue  juices  across 
the  cell  membrane.  The  extent  and  character  of  this  exchange  depend 
on  many  circumstances,  some  affecting  the  cell  wall,  others,  the  osmotic 
and  other  properties  of  the  two  fluids.  Obviously,  the  function  of  the 
circulation  is  to  maintain  the  tissue  fluids  of  correct  composition,  the 
blood  plasma  serving  to  carry  food  materials  and  dissolved  oxygen  to 
them  (see  page  380),  but  being  assisted  in  the  opposite  function  of  re- 
moval of  effete  products  by  the  lymph.  The  lymph  is  purely  a  scavenger; 
the  blood  is  both  purveyor  and  scavenger. 

The  above1  description  of  the  lymphatics  is  not  universally  accepted 
by  anatomists,  certain  of  whom  believe  that  the  lymphatics  are  developed 
from  tissue  spaces  and  are  consequently  much  more  extensive  than  they 
appear  to  be  from  injected  specimens.  The  above  conclusions  are  based  on 
reconstruction  models,  made  from  serial  sections  of  embryonic  tissues, 
in  which  the  lymphatics  frequently  appear  as  isolated  vesicles  without 
visible  connections.  The  failure  of  injections  to  penetrate  into  the  re- 
moter parts  of  such  a  lymphatic  system  in  the  embryo  is  attributed  to 
the  discontinuity  of  spaces,  which  is,  however,  removed  at  later  stages 
of  development. 

The  manner  of  absorption  of  injected  fluids  does  not,  however,  sup- 
port the  view  that  the  lymphatics  are  directly  connected  with  the  tis- 
sue spaces.  When  all  the  structures  of  a  part  are  ligated  except  the 
main  artery  or  vein,  injected  poisons  which  affect  central  structures, 
such  as  the  nerve  centers,  develop  their  action  as  quickly  as  in  the  in- 
tact animal  (e.g.,  strychnine).  Similarly,  when  pigments  such  as  meth- 
ylene blue  are  injected  into  the  pleural  cavity  or  subcutaneously,  they 
appear  in  the  mine  long  before  the  lymph  of  the  thoracic  duct.  Such 
results  indicate  the  pathway  of  absorption  to  be  the  blood  rather  than 
the  lymph  vessels.  Through  this  latter  channel  absorption  proceeds 
more  slowly,  but  can  be  greatly  assisted  by  massaging  the  site  of  injec- 
tion. When  colored  solutions,  such  as  India  ink  or  carmine,  are  injected 
subcutaneously,  however,  a  very  perfect  injection  of  the  neighboring 
lymphatics  may  ultimately  occur,  and  through  the  same  pathways  mi- 
croorganisms spread  from  an  infected  area. 


118  THE   BLOOD   AND    THE   LYMPH 

EXPERIMENTAL  INVESTIGATIONS 

It  has  proved  a  most  difficult  problem  to  gain  any  exact  knowledge 
of  the  production  of  lymph  by  experimental  means.  Starling,  some  years 
ago,  in  repeating  many  of  the  experiments  of  older  physiologists  in  the 
light  of  the  newer  facts  of  physical  chemistry,  added  much  that  is  of 
interest,  and  it  is  chiefly  with  his  work  that  we  will  concern  ourselves 
here. 

The  unequal  lymph  supply  of  different  regions  of  the  body  is  strik- 
ingly demonstrated  by  comparing  the  lymph  flow  from  the  lymphatics 
of  the  leg  with  that  from  the  thoracic  duct.  No  lymph  flows  from  the 
former  unless  the  muscles  are  thrown  into  activity  or  the  blood  is  pre- 
vented from  leaving  the  limb  by  ligaturing  all  the  veins.  Changes  in  the 
arterial  blood  pressure  do  not  affect  the  flow.  On  the  other  hand,  a  great 
increase  in  the  flow  from  the  thoracic  duct  can  readily  be  induced  by 
disturbances  in  the  blood  supply.  Obstruction  of  the  portal  vein,  for 
example,  immediately  increases  the  lymph  flow  four  or  five  times  because  of 
venous  congestion  in  the  intestinal  capillaries,  whilst  a  still  greater 
increase — perhaps  tenfold — is  induced  by  obstruction  to  the  inferior  vena 
cava,  which  raises  the  capillary  pressure  in  both  the  liver  and  the  intes- 
tines. After  ligation  of  the  hepatic  lymphatics  (at  the  hepatic  pedicle), 
obstruction  of  the  vena  cava  no  longer  causes  the  outflow  of  lymph  to 
increase,  indicating  that  the  lymph  in  the  last  mentioned  experiment 
must  have  come  from  the  hepatic  lymphatics. 

These  results,  so  far  as  they  go,  could  be  satisfactorily  explained  on 
the  basis  that  lymph  formation  is  a  filtration  process,  that  is,  a  process 
dependent  upon  difference  in  mechanical  pressure  between  the  blood 
capillaries  and  the  tissue  spaces.  The  lymphatics  would  then  serve  as 
channels  to  return  this  fluid  to  the  blood  vessels  through  the  thoracic 
duct.  The  difference  in  the  magnitude  of  the  increased  lymph  flow  from 
increase  in  capillary  pressure  in  different  regions  would  be  dependent 
on  the  permeability  of  the  filter,  the  capillaries  of  the  limbs  being  much 
less  permeable  than  those  of  the  intestine,  and  particularly  of  the  liver. 
Another  fact  in  conformity  with  this  view  concerns  the  composition  of 
the  lymph  from  the  two  regions,  that  from  the  limb  lymphatics  being 
poor  in  protein,  whereas  that  from  the  thoracic  duct  does  not  fall  far 
behind  the  blood  plasma  in  this  regard. 

Although  filtration  may  explain  the  considerable  increase  in  lymph 
flow  produced  by  extreme  changes  in  capillary  pressure,  it  by  no  means 
suffices  to  explain  lymph  formation  under  less  abnormal  conditions. 
When  a  muscle  or  a  gland  is  at  rest,  it  produces  practically  no  lymph, 


LYMPH    FORMATION   AND    CIRCULATION  119 

but  during  activity  the  flow  becomes  marked.  This  can  not  be  explained 
by  filtration,  but  may  be  accounted  for  by  a  physico-chemical  process — 
namely,  osmosis.  The  energy  required  for  the  activity  of  the  tissue 
cell  is  produced  by  chemical  changes,  whereby  large  molecules  become 
broken  down  into  numerous  smaller  ones.  These  smaller  molecules  are 
then  discharged  into  the  surrounding  tissue  fluids,  the  osmotic  pressure 
of  which  they  increase,  with  the  consequence  that  water  is  attracted 
by  osmosis  from  the  plasma  in  the  blood  capillaries  (see  page  4).  This 
increases  the  volume  of  tissue  fluid,  which  is  then  drained  away  by  the 
lymphatics.  The  increase  in  molar  concentration  Avill  also  affect  the 
tissue  juices,  tending  to  make  the  cell  swell  up  by  absorbing  water. 
In  gland  cells  this  extra  water  is  immediately  extruded  to  form  the 
water  of  the  secretion  (see  page  421). 

An  analogous  method  of  lymph  formation  is  not  confined  to  situations 
where  the  capillaries  are  relatively  impermeable,  for  it  also  occurs  in 
the  liver,  the  lymph  flow  from  which  is  greatly  increased  by  the  injec- 
tion of  bile  salts.  A  similar  process  no  doubt  results  from  muscular 
activity,  although  in  this  case  the  tissue  spaces  must  form  a  continuous 
system  of  their  own,  there  being,  according  to  most  authorities,  no 
lymphatics. 

.  Considerable  interest  has  been  taken  in  the  stimulating  effect  which 
certain  chemical  substances  have  on  the  secretion  of  lymph  from  the 
thoracic  duct.  These  so-called  lymphagogues  belong  to  two  classes — ■ 
crystalline  and  colloidal.  Of  the  former,  glucose,  urea,  and  sodium 
chloride  in  hypertonic  solution,  are  the  best  known.  Starling  explains 
their  action  as"  dependent  upon  an  increase  in  the  osmotic  pressure  of 
the  blood.  This  attracts  water  into  the  blood  from  the  tissue  juices, 
and  leads  to  an  hydremic  plethora,  with  a  consequent  increase  in  capil- 
lary pressure.  If  the  blood  pressure  is  lowered  by  hemorrhage  before 
the  hypertonic  solution  is  injected,  very  little  stimulation  of  lymph  flow 
occurs,  because  there  is  no  available  fluid  in  the  tissue  to  produce  the 
plethora.  This  observation  does  not,  however,  very  strongly  support 
the  explanation,  because  so  many  other  disturbances  may  result  from 
hemorrhage. 

The  colloidal  lymphagogues  include  watery  extracts  of  the  dried  tis- 
sues of  leeches,  crayfish,  and  mussels,  as  well  as  commercial  peptone. 
They  probably  act  by  damaging  the  endothelium  of  the  capillaries,  so 
that  filtration  occurs  more  readily.  Although  their  action  is  displayed 
more  particularly  on  the  lymphatics  of  the  liver  and  intestines,  it  is  also 
apparent  on  the  skin  capillaries,  producing  cutaneous  edema,  and  the 
formation  of  blisters  (nettle  rash). 


120  THE    BLOOD   AND    THE   LYMPH 


EDEMA 


With  such  an  imperfect  knowledge  concerning  the  physiology  of 
lymph  formation,  it  is  not  surprising  that  the  causes  of  excessive  accu- 
mulation of  flwid  in  and  between  the  tissue  elements  should  be  little  un- 
derstood. All  of  the  conditions  which  have  been  mentioned  as  capable 
of  causing  an  increased  secretion  of  lymph — such  as  increase  in  capillary 
pressure,  hydremic  plethora,  action  of  poisons  on  the  endothelium — are 
likely  to  cause  edema  if  the  lymphatics  of  the  part  are  simultaneously 
obstructed.  To  produce  in  animals  edema  of  the  subcutaneous  tissues 
like  that  observed  clinically,  it  is,  however,  necessary  that  the  vascular 
disturbance  be  accompanied  either  by  local  damage  to  the  capillary 
endothelium,  such  as  is  produced  by  arsenic  or  uranium;  or  by  a  gen- 
eral toxemic  condition,  such  as  is  set  up  by  nephritis.  When  large 
amounts  of  saline  solution  are  injected  intravenously,  extensive  ex- 
travasation of  fluid  may  occur  into  the  liver,  peritoneum  and  intestinal 
lumen,  without  any  subcutaneous  edema. 

Clinical  edemas  are  of  at  least  three  types: 

1.  The  inflammatory  edemas,  in  which  the  fluid  permeates  the  cells  of 
the  inflamed  area  and  does  not  shift  to  other  parts  of  the  body  under 
the  influence  of  gravity. 

2.  The  nephritic  edemas,  in  which  the  fluid  is  more  or  less  loose  in  the 
subcutaneous  tissues  and  readily  changes  its  position,  and  which  is 
accompanied  by  excess  of  water  in  the  blood  with  a  corresponding  in- 
crease of  sodium  chloride;  the  percentage  concentration  of  sodium  chlo- 
ride in  the  blood  remains  unchanged,  but  that  the  other  constituents 
diminished. 

3.  Cardiac  edemas,  which  are  also  hypostatic,  but  are  unaccompanied 
by  changes  in  the  relative  amount  of  water  and  sodium  chloride  in  the 
blood. 

The  second  and  third  varieties  of  edema  may  of  course  be  more  or 
less  present  together,  for  the  kidneys  are  likely  to  become  secondarily 
affected  during  venous  stasis. 

The  salt  retention  in  nephritic  edema  is  very  significant.  As  ex- 
plained elsewhere,  it  is  revealed  by  comparing  the  daily  output  of  so- 
dium chloride  by  the  urine  with  the  concentration  of  this  salt  in  the 
blood.  Less  salt  is  eliminated  than  Avould  be  the  case  in  a  normal  in- 
dividual with  the  same  percentage  of  salt  in  the  blood.  In  many  cases 
also  edema  can  be  diminished  by  withholding  salt  from  the  food.  Widal 
and  Javal  have  conclusively  shown  the  relationship  of  retention  of  water 
in  the  body,  as  judged  by  variations  in  body  weight,  to  the  hydremic 
condition,  as  judged  by  the  refractive  index  of  the  blood  serum,  and 


LYMPH    FORMATION    AND   CIRCULATION  121 

to  the  amounl   of  suit   in  the  diet.     A   very  considerable   retention   of 

water  usually  occurs  before  there  is  any  evidence  of  edema;  indeed,  as 
a  result  of  giving  salt,  the  body  weigh.1  may  increase  From  live  to  sever, 
kilograms  (10  to  L5  pounds)  within  a  day  or  two  without  the  appear- 
ance of  pufliness. 

The  cause  of  the  edema  during  salt  retention  is  no  doubt  closely  re- 
lated to  the  action  of  lymphagogues.  In  a  normal  person  excessive  in- 
gestion of  salt  is  immediately  followed  by  excretion  of  the  excess  through 
the  kidney.  Where  the  kidneys  are  diseased,  this  excess  of  salt  is  re- 
tained in  the  bloodj  raising  its  osmotic  pressure  and  attracting  Avater 
from  the  tissue  fluids.  This  leads  to  excessive  thirst,  the  imbibed  "water 
being  used  to  replace  that  lost  from  the  tissues.  But  all  the  crystalline 
Lymphagogues  do  not,  when  present  in  excess  in  the  blood  of  nephritic 
patients,  necessarily  cause  edema;  urea,  for  example,  may  accumulate 
considerably  without  any  such  effect.  The  different  action  is  usually 
attributed  to  inequality  in  the  diffusibility  of  the  two  crystalloids  through 
animal  membranes,  sodium  chloride  diffusing  much  less  readily  than 
urea. 

It  is  most  important  to  note  that  the  fluid  in  edema  is  loose  in  the 
tissues  and  can  be  drained  away  by  the  insertion  of  tubes.  There  is 
absolutely  no  evidence  in  support  of  the  claim  of  Martin  Fischer  that 
edema  is  due  to  imbibition  of  water  by  the  colloids  of  the  tissues.  This 
question  has  been  fully  discussed  elsewhere  (page  C2). 

BLOOD  AND  LYMPH  REFERENCES 

(Monographs) 

iHowell,  W.  H.:     The  Harvey  Lectures,  J.  B.  Lippincott  Co.,  xii,  272. 

^Starling,  E.  H.:     Human  Physiology,  Lea  &  Febiger,  1915. 

sKowe,  A.  II.:     Arch.  Int.  Med.,  1917,  xix,  354, 

^Williamson,  C.  S.:     Arch.  Int.  Med.,  1916,  xviii,  505. 

•■Tower  and  Herni:     Proc.  Soc.  Biol,  and  .Mel.,   1916,  xviii,  505. 

"Rous  and  Robertson:     Jour.  Exp.  Med.,   1916,  xxiii,  219,  239,  549. 

TButlcr,  G.  G.:     Quart.  Jour.  Med.,  1912,  vi,  145. 

sHo\\cll,  W.  II.:     cf.  Harvey  Lecture;  also  Am.  Jour.  Physiol.,   1913,  xxxii.  264. 

'-•Drinker,  C.  K.,  and  K.  P.:     Am.  Jour.  Physiol.,  1916,  xii,  .">. 
loDenny    ami    Minot:      Arch.   Int.    Med.,    1916,    xvii,    101;    Am.    Jour.    Physiol.,    1915, 

xxxviii,  233. 
"Addis,  T.:     Quart.  Jour.  Med.,  1910,  iv,  14. 

3-<'annon  and  Mendenhall:     Am.  .Jour.  Physiol.,  1914,  xxxiv,  225. 
i    Unwell,  W.  H.:     Arch,   Int.  Med.,  1914,  xiii,  80. 
"p,rodie.  T.  G.:     Jour.  Physiol.,  1897,  xxi,  403. 

"Whipple,  G.  II.:     Arch.  Int.  Med.  1912,  ix,  3(55;  Jour.  Exp.  Med..  1911,  xiii,   136. 
"Whipple,  G.  H.:     Arch.  Int.  Med.,  1913,  xii,  637. 
"Duke,  W.  W.:     Arch.  Int.  Med.,  1912,  ix,  258. 


PART  III 
THE  CIRCULATION  OF  THE  BLOOD 


CHAPTER  XV 

BLOOD  PRESSURE 

The  object  of  the  circulation  is  to  maintain  through  the  tissues  a  sup- 
ply of  blood  that  is  adequate  to  meet  their  demands  for  nutriment  and 
oxygen  and  to  remove  the  effete  products  of  their  metabolism.  The  de- 
mands vary  according  to  the  activities  of  the  tissue,  being  particularly 
variable  in  the  case  of  such  tissues  as  the  muscular  and  the  glandular. 
Tn  studying  the  physiology  of  the  circulation  Ave  have  therefore  to  bear 
in  mind  two  aspects  of  the  problem:  (1)  the  cause  for  the  continuous 
bloodflow,  and  (2)  the  mechanism  by  which  alterations  in  this  bloodflow 
are  brought  about. 

Tf  we  open  an  artery  we  shall  find  that  the  blood  escapes  from  it 
under  such  a  pressure  that  it  is  thrown  to  a  height  of  about  six  feet, 
that  its  outflow  is  proportional  to  the  size  of  the  artery,  and  that  it  pul- 
sates. If,  on  the  other  hand,  we  open  a  vein,  we  shall  find  that  the 
blood  wells  out  without  any  very  evident  pressure,  and  that  it  flows 
in  a  continuous  stream,  its  outflow  being  the  same  in  a  unit  of  time  as 
that  of  the  artery,  provided  the  two  vessels  are  the  only  ones  supplying 
the  particular  area.  The  general  conditions  governing  the  bloodflow 
are  the  same  as  those  governing  the  flow  of  fluid  through  any  system  of 
tubes.  For  example,  in  the  city  water  mains  it  is  known  to  every  one 
that  the  rate  of  outflow  from  any  part  of  the  system  depends  finally  on 
two  factors:  (1)  the  difference  in  pressure  at  the  beginning  and  end  of 
the  system,  and  (2)  the  caliber  of  the  tube  at  the  outlet.  We  may  in- 
crease the  outflow  by  raising  the  pressure  at  the  beginning  of  the  system, 
the  caliber  of  the  outlet  meanwhile  remaining  constant,  or  we  may 
maintain  the  pressure  constant  but  increase  the  caliber  of  the  outlet. 

In  the  circulation  of  the  blood,  the  difference  in  pressure  at  the  be- 
ginning and  end  of  the  circulation  is  furnished  by  the  pumping  action 
of  the  heart,  and  the  alteration  of  the  caliber  of  the  outlet  is  provided 
for  by  the  constriction  or  dilatation  of  the  blood  vessels.  These  simple 
physical  principles  indicate  the  direction  which  a  study  of  the  circulation 

122 


I'.UHM)    l-KKKSUKK  123 

should  take.  They  indicate  that  our  first  consideration  should  be  of  the 
mean  blood  pressure,  bow  it  is  maintained,  and  how  it  can  be  made  to 
vary.  After  we  have  learned  this,  we  may  then  proceed  to  a  more 
particular  examination  of  the  mechanism  of  the  pump — that  is,  of  the 
heartbeat;  then  finally  we  may  proceed  to  examine  the  nature  of  the 
processes  by  which  the  caliber  of  the  arteries  is  controlled. 

THE  MEAN  ARTERIAL  BLOOD  PRESSURE 

The  first  prerequisite  to  the  investigation  of  the  blood  pressure,  as  of 
any  other  physical  problem,  is  that  we.  should  possess  some  means  by 
which  it  can  be  quantitatively  measured.  The  earliest  attempt  to  accom- 
plish this  was  made  by  the  English  scientist,  the  Rev.  Stephen  Hales,  a 
little  over  a  century  after  Harvey  published  his  account  of  the  circula- 
tion of  the  blood.  Hales  connected  a  glass  tube  nine  feet  in  length  with 
a  severed  artery  of  a  horse,  the  connection  between  the  two  being  made 
by  means  of  a  piece  of  brass  pipe  joined  to  the  windpipe  of  a  goose  as  a 
substitute  for  rubber  tubing.  He  found  on  untying  the  ligature  on  the 
artery  that  the  blood  rose  in  the  tube  to  a  height  of  eight  feet  and  three 
inches  above  the  level  of  the  left  ventricle  of  the  heart,  and  that  when 
at  full  height  it  rose  and  fell  with  each  pulse  through  a  distance  of  two, 
three  or  four  inches. 

Mercury  Manometer  Tracings 

The  somewhat  crude  but  very  significant  experiment  of  Hales  clearly 
established  the  existence  of  the  enormous  pressure  at  which  the  blood  is 
made  to  circulate  through  the  arteries.  To  render  possible  a  further 
investigation  of  the  factors  on  which  this  pressure  depends,  it  became 
necessary  to  invent  some  more  convenient  means  for  its  measurement, 
but  this  was  not  accomplished  until  a  century  later,  when  Poiseuille  ap- 
plied the  mercury  manometer,  which  Ludwig  subsequently  adapted  so 
that  tracings  might  be  taken  (Fig.  21). 

Having  before  us  such  a  tracing  as  shown  in  Fig.  22,  let  us  consider 
how  it  may  be  used  in  the  study  of  blood  pressure.  The  first  thing  we 
must  do  is  to  measure  the  average  height  of  the  tracing  above  the  line  of 
zero  pressure;  the  mean  arterial  blood  pressure  is  then  equal  to  this 
distance  multiplied  by  two,  because  the  distance  through  which  the  mer- 
cury has  moved  up  in  the  limb  of  the  manometer  carrying  the  writ- 
ing point  is  only  one-half  of  its  total  displacement.  Since  mercury 
is  about  13.5  times  heavier  than  an  equal  volume  of  blood,  the  above 
measurement  must  be  multiplied  by  this  figure  if  we  desire  to  express 


124 


THE    CIRCl'LATIOX    OF    THE    BLOOD 


our  result  in  terms  of  the  height  to  which  the  blood  pressure  could  raise 
a  column  of  blood. 

In  arteries  of  approximately  the  same  size,  the  mean  arterial  blood 
pressure  does  not  markedly  vary  in  different  mammals.  Thus,  in  the 
carotid  artery  of  the  dog  it  averages  about  110  to  120  mm.  Hg,  in  that 
of  the  eat  about  105  to  115  mm.,  in  the  rabbit  from  90  to  105  mm.,  in 
the  sheep  about  150  mm.,  in  the  horse  about  200  mm.,  and  in  man  some- 


Fig.  21. — Mercury  manometer  and  signal  magnet,  arranged  for  recording  the  mean  arterial 
blood  pressure  in  a  laboratory  experiment.  The  pressure  bottle  (R)  is  filled  with  anticoagulating 
fluid  and  is  connected  by  tubing  with  the  manometer  (M),  the  cannula  for  the  artery  ( I' )  being 
connected  with  the  T-piece  (J).  By  this  arrangement  it  is  possible  to  flush  out  the  tubing 
when    clotting    interferes    with    the    experiment      (From    Jackson — Experimental    Pharmacology.) 


where  between  120  and  140  mm.  The  pressure  varies  in  different  parts 
of  the  vascular  system,  being  greatest  in  the  aorta  and  least  in  the  small- 
est arterioles  but  the  fall  in  pressure — the  pressure  gradient — does  not 
become  very  pronounced  until  the  arterioles  have  become  so  small  that 
it  is  no  longer  possible  to  insert  a  cannula  into  them;  thus,  the  mean 


IU.OOD    I'iiKKSIKi: 


12.-) 


blood  pressure  in  the  renal  or  femoral  artery  is  very  little  less  than  that 
in  the  aorta. 

If  we  examine  ihc  contour  of  the  tracing  which  the  pressure  draws,  we 
shall  find  llial  it  exhibits  two  types  of  wave,  small  and  large;  and  if  we 
observe  the  animal  while  the  tracing  is  being  taken,  we  shall   find  that 


Fig.  22. — The  arterial  blood  pressure  recorded  with  a  mercury  manometer  (lower  tracing), 
along  with  a  tracing  of  the  respiratory  movement  of  the  thorax.  Note  that  the  beginning  of 
respiration    occurs    distinctly    before  "the    rise    in    blood    pressure. 


the  former  are  caused  by  the  heartbeats  and  the  latter  by  the  respira- 
tions— an  observation  which  immediately  raises  the  question  as  to  the 
trustworthiness  of  the  method,  for  it  will  be  asked,  How  can  it  be  that 
the  heartbeat  produces  an  effect  on  blood  pressure  which  is  less  than 
that  of  the  respirations?  Obviously  the  tracing  must  be  faulty  in  re- 
gard to  the  relative  significance  of  the  waves. 


126 


THE    CIRCULATION    OP    THE   BLOOD 


Spring  Manometer  Tracings 

The  cause  of  this  inaccuracy  depends  on  the  inertia  of  the  mercury, 
an  inertia  which  is  so  great  that  the  sudden  changes  of  pressure  produced 
by  each  heartbeat  are  not  able  to  overcome  it,  whereas  the  much  less 
significant  but  more  prolonged  pressure  changes  produced  by  each  respi- 
ration develop  their  full  effect  on  the  mercury.  These  facts  led  investi- 
gators to  seek  for  instruments  in  which  the  inertia  error  is  eliminated, 
with  the  result  that  they  invented  what  are  known  as  spring  manometers. 


Fig.    23. — Ilurthle's    spring    manometer. 


Many  varieties  of  this  instrument  have  been  produced,  but  for  our  pur- 
pose it  is  necessary  to  describe  the  principle  of  only  the  simplest  and 
most  efficient — the  Hiirthle  manometer.  As  shown  in  Fig.  23,  it  consists 
of  a  variety  of  tambour,  which  differs  from  the  ordinary  tambour  in  two 
important  particulars:  (1)  its  chamber  is  made  as  small  as  possible,  and 
(2)  it  is  covered  not  with  an  elastic  membrane  but  with  one  of  leather  or  of 
thin  fluted  metal.  These  two  precautions  are  taken  in  order  to  avoid  spuri- 
ous waves  set  up  on  account  of  elastic  recoil.  Such  errors  are  further 
reduced  by  filling  the  tubing  and  chamber  of  the  tambour  with  an  anti- 
coagulating  fluid. 


Fig.    24. — Arterial    pressure    recorded    by    a    spring    manometer.      The    effect    of    weak    excitation    of 
the    vagus    is    seen    during    the    period    marked    by    the    signal     m.       (From    Dubois.) 


Before  the  tracing  taken  with  the  spring  manometer  can  be  em- 
ployed for  quantitative  measurements,  it  must  obviously  be  graduated 
according  to  some  scale.  This  is  accomplished  immediately  before  or 
after  the  experiment  by  connecting  the  manometer  through  a  T-piece 
with  a  pressure  bottle,  which  can  be  raised  or  lowered  to  a  specified 
height,  and  with  a  mercury  manometer.  The  displacement  of  the  writing 
point  of  the  spring  manometer  corresponding  to  each  10  mm.  Hg  of 
pressure  is  then  written  on  the  tracing. 


W,0()l>    I'RKSSIIRK 


127 


The  tracings  taken  with  such  a  manometer,  as  shown  in  Fig.  24,  are 
quite  different  from  those  with  the  mercury  manometer.  It  will  be  seen 
that  now  the  cardiac  waves  are  decidedly  the  more  pronounced,  the  respira- 
tory, being  comparatively  inconspicuous.  Instead  of  there  being  a  fairly 
steady  pressure  in  the  arteries,  this  undergoes  very  considerable  altera- 
tion during  each  heartbeat.* 

Examination  of  this  tracing  gives  us  accurate  information  regarding 
the  blood  pressure  both  between  the  heartbeats — diastolic,  as  it  is  called — 
and  during  them — systolic.  It  gives  us  a  means  of  telling  what  must  be 
the  dead  load  of  the  circulation — that  is,  the  pressure  that  is  constantly 
present — as  well  as  the  live  load  that  is  superadded  to  this  by  each  heart- 


Fig.  25. — Diagram  based  on  experiments  on  dogs  to  show  the  magnitude  of  the  systolic, 
diastolic  and  mean  blood  pressures  at  different  parts  of  the  circulatory  system.  O  is  the  line 
of  zero  pressure,  and  the  letters  below  it  indicate  the  parts  of  the  system  to  which  the  curves 
refer.      (From    Brubaker.) 


beat.  This  difference  is  often  called  the  pressure  pulse,  and  in  man  it 
amounts  to  somewhere  about  35  mm.  Hg.  If  we  take  tracings  with  a 
spring  manometer  from  different  parts  of  the  arterial  tree,  we  shall  find 
that,  as  we  travel  towards  the  periphery,  the  pressure  pulse  becomes  less 
and  less  marked,  until  finally  by  the  time  the  capillaries  are  reached  it 
has  almost  entirely  disappeared.  This  decline  in  the  pressure  pulse  can 
moreover  be  seen  to  be  dependent  more  largely  on  a  fall  in  systolic  than 
in  diastolic  pressure.  In  other  words,  the  dead  load  of  the  circulation — 
the  diastolic  pressure — remains  practically  constant  all  along  the  arte- 
rial tree,  whereas  the  systolic  pressure  falls  relatively  quickly  (Fig.  25). 


*The   tracings   shown   in    Figs.    22   and   24  are    not   typical,    ihe   pulse   pressure   being   too   small    in 
the  latter  and  too  large  in  the  former. 


128  THE    CIRCULATION    OF    THE    BLOOD 

Clinical  Measurements 

The  methods  of  blood-pressure  measurement  in  man  have  recently 
become  so  perfected  that  the  results  are  almost  as  accurate  as  those  ob- 
tained in  laboratory  animals  by  direct  measurement  through  the  use  of 
cannula;  inserted  into  the  vessels.  Both  the  systolic  and  the  diastolic 
pressure  can  be  measured  with  equal  facility  and  accuracy.  Since  the 
technic  for  making  the  systolic  measurements  was  described  at  a  much 
earlier  date  than  that  for  the  diastolic,  it  has  until  recently  been  the 
habit  with  a  great  part  of  the  medical  profession  to  be  satisfied  with 
systolic  readings  alone.  This  is  most  unfortunate,  because  the  knowledge 
which  such  information  gives  us  is  incomparably  inferior  to  that  which 
can  be  obtained  by  gauging  the  diastolic  pressure.  Until  we  have  learned 
more  about  the  dynamics  of  circulation,  it  would  be  profitless  to  go 
into  any  details  as  to  the  reasons  for  this  statement,  but  it  will  soon 
become  self-evident.  Suffice  it  for  the  present  to  state  that  the  diastolic 
pressure  is  the  more  important  hecause  it  gives  us  the  load  which  the  ves- 
sels and  aortic  valves  must  constantly  hear,  and  the  resistance  which  must 
be  overcome  prior  to  the  opening  of  these  valves  at  the  beginning  of 
systole.     Moreover,  it  helps  us  to  gauge  the  peripheral  resistance. 

The  first  step  in  the  technic  of  blood-pressure  measurements  in  man 
is  the  placing  of  an  armlet  or  cuff  around  the  arm  or  leg.  This  armlet 
consists  of  a  rubber  bag  at  least  12  cm.  broad  and  covered  on  its  outer 
surface  by  cloth  or  leather.  The  bag  is  connected  by  tubing  with  a  pres- 
sure gauge  and  a  pump.  The  pressure  gauge  may  be  either  an  ordinary 
mercury  manometer  or  one  of  the  numerous  gauges  built  on  the  aneroid 
principle  that  are  now  on  the  market  (Fig.  26).  For  measuring  the 
blood  pressure  in  the  vessels  of  the  upper  extremities,  the  armlet  should 
be  applied  around  the  fleshy  part  of  the  upper  arm  and  for  the  lower 
limbs  around  the  thigh.  For  accurate  reading  of  both  pressures  the 
following  procedure  should  be  folloAvcd.  Having  applied  the  armlet,  the 
pulse  should  be  palpated  at  the  radial  artery,  and  the  pressure  in  the 
armlet  then  raised  until  the  pulse  can  no  longer  be  felt,  at  which  moment 
the  pressure  in  the  manometer  should  be  noted.  The  cuff  should  then  be 
slowly  decompressed  and  the  pressure  noted  at  which  the  pulse  reappears. 
These  two  readings  of  systolic  pressure  should  be  close  together,  but 
they  will  not  usually  agree  exactly  for  reasons  which  will  be  explained 
immediately.  They  give  us  the  palpatory  systolic  index,  as  it  is  called. 
The  pressure  is  now  lowered  about  15  mm.  Ilg,  and  a  stethoscope  is 
placed  in  front  of  the  bend  of  the  elbow  over  the  artery  and  as  close  up 
to  the  cuff  as  possible.  With  each  heartbeat  a  distinct  sound  like  a  pistol 
shot  will  be  heard.  The  decompression  is  now  continued  slowly,  and  as 
the  pressure  falls  the  sounds  will  be  heard  to  become  louder  and  prob- 


1U.OOD    PRESSURE 


129 


ably  somewhal  murmurish  in  quality.  At  a  certain  pressure  this  loud 
character  of  the  sound  will  suddenly  become  much  less  marked,  and  the 
murmurish  quality  if  presenl  will  suddenly  disappear.  Tins  point  cor- 
responds to  the  diastolic  pressure,  which  is  now  read  off  from  the 
manometer. 

It  must  be  remembered  that  below  this  point,  as  the  pressure  in  the 
cuff  is  further  lowered,  a  sound  is  still  heard  in  the  artery;  indeed  it 
does  not  entirely  disappear  until  the  pressure  has  become  quite  low.  This 
point  of  final  disappearance  is,  however,  of  no  significance.    The  cuff  is 


Fig.  26. — Apparatus  for  measuring  the  arterial  blood  pressure  in  man.  The  pressure  in  the 
cuff  is  ra:sed  by  means  of  the  syringe  until  the  pulse  can  no  longer  be  felt  at  the  wrist.  This 
pressure   is   read    off   on   the   mercury    manometer    (systolic    pressure). 

now  entirely  decompressed,  and  should  be  left  so  for  a  moment  or  more, 
so  that  the  circulation  in  the  part  of  the  arm  below  it  may  return  to  the 
normal. 

The  above  readings  should  then  be  controlled  by  a  second  observa- 
tion, in  which  the  methods  employed  are  slightly  modified.  With  the 
stethoscope  at  the  bend  of  the  elbow  the  pressure  in  the  cuff  is  run  up  to 
a  little  above  the  previously  determined  diastolic  pressure,  so  that  the 
sound  is  clearly  heard.  The  pressure  is  then  further  raised  till  the 
sound  disappears.    This  point  indicates  the  systolic  pressure;  it  is  called 


130  THE    CIRC  I  ELATION    OF    THE    KLOOD 

the  auditori/  systolic  index.  It  will  be  found  to  give  a  systolic  pressure 
a  little  higher  than  that  obtained  by  palpation  of  the  artery  at  the  wrist. 
The  sound  being  now  absent,  the  pressure  in  the  cuff  is  lowered  until 
the  sound  reappears,  and  the  point  at  which  this  occurs  should  almost 
exactly  correspond  to  that  at  which  the  sound  was  found  to  disappear. 
If  the  palpatory  systolic  index  is  not  below  the  auditory,  it  indicates 
that  some  error  has  been  made  in  the  application  of  the  apparatus,  and 
that  the  reading  of  the  diastolic  pressure  will  be  unreliable.  The  usual 
source  of  error  is  in  the  position  of  the  stethoscope.  If  readjustment  of 
this  does  not  bring  the  two  indices  into  proper  relationship,  the  auscul- 
tatory method  can  not  be  relied  upon  for  either  systolic  or  diastolic 
readings. 

In  case  of  the  failure  of  the  auscultatory  method,  we  have  to  fall  back 
upon  the  palpatory  method  for  systolic  pressure;  and  for  the  measure- 
ment of  diastolic,  Ave  have  to  use  the  method  known  as  the  oscillatory, 
which  until  recent  years  was  the  only  one  used  for  gauging  the  dias- 
tolic pressure.  This  consists  in  observing  the  oscillation  of  the  indicator 
of  the  pressure  gauge ;  as  the  pressure  in  the  cuff  falls  gradually  from 
below  the  systolic  pressure,  these  oscillations  will  be  observed  to  increase 
in  amplitude,  until  they  reach  a  maximum  beyond  which  with  lower 
pressure  they  rapidly  decline.  The  pressure  in  the  cuff  at  the  moment 
when  the  oscillations  are  at  the  maximum  represents  the  diastolic  pres- 
sure. With  a  mercury  instrument  it  is  obviously  difficult  to  employ  this 
method,  but  with  a  modern  spring  instrument  it  can  with  a  little  practice 
be  used  with  great  accuracy  and  will  serve  as  a  valuable  check  on  the 
diastolic  reading  as  taken  by  the  auscultatory  method. 

The  procedure  may  be  altered  in  various  ways,  there  being  only  one  pre- 
caution to  bear  in  mind ;  namely,  that  the  pressure  in  the  cuff  should  not  be 
applied  continuously  for  more  than  a  few  moments  of  time,  for  if  this 
is  done  for  long  periods,  not  only  will  it  interfere  with  the  accuracy 
of  the  reading,  but  it  may  cause  considerable  discomfort  to  the  patient. 

There  are  several  conditions  affecting  the  accuracy  of  the  readings  by 
each  method  which  it  is  well  to  bear  in  mind.  These  have  been  investi- 
gated by  MacWilliam,1  Leonard  Hill,2  and  Erlanger.3  With  regard  to 
the  systolic  pressure  the  most  important  of  these  are  as  follows:  (1)  The 
compression  cuff  should  be  a  wide  one  (12  cm.),  and  it  should  never  be 
applied  so  that  there  is  any  chance  of  its  compressing  the  artery  against 
a  bony  surface.  This  precaution  is  necessary,  since  it  has  been  found  that 
much  less  pressure  is  required  to  obliterate  any  perceptible  pulse  below 
the  armlet  when  the  artery  is  flattened  against  some  hard  structure  than 
when  it  is  uniformly  compressed  in  the  tissues  in  which  it  lies.  (2)  Dis- 
crepancies are  often  noted  between  the  systolic  readings  on  compres- 


BLOOD    PRESSURE  131 

sion  and  decompression  of  the  artery;  thai  is,  the  pulse  may  reappear  on 
decompression  at  a  lower  pressure  than  that  at  which  it  disappeared  <»n 

compression,  the  difference  being  most  marked  -when  the  decompression 
is  done  quickly.  This  difference  is  owing  to  the  fact  that  the  full  force 
of  the  pulse  does  not  reach  the  forearm  until  all  the  vessels  have  become 
distended  with  blood.  (3)  There  are  often  discrepancies  in  the  systolic 
readings  taken  from  different  limits;  thus,  il  is  not  uncommon  to  find 
that  the  systolic  pressure  in  the  leg  is  higher  than  that  in  the  arm  even 
when  the  observed  person  is  in  the  horizontal  position.  These  differences 
are  most  commonly  observed  in  patients  suffering  from  aortic  regurgi- 
tation or  thickened  arteries.  In  aortic  regurgitation  the  pulse  is  of  the 
water-hammer  variety,  and  the  greater  systolic  pressure  observed  in  the 
leg  vessels  in  such  cases  seems  to  depend  on  differences  in  the  phys- 
ical conditions  concerned  in  the  transmission  of  this  exaggerated  pulse 
wave  to  the  vessels  of  the  two  extremities. 

The  reason  for  the  discrepancies  in  cases  of  hardened  arteries  is  no 
doubt  that  the  hardening  is  likely  to  be  more  pronounced  in  the  ves- 
sels of  the  thigh  than  in  those  of  the  arms.  When  a  hardened  vessel  is 
compressed  it  does  not  collapse  uniformly — that  is,  it  does  not  become 
completely  closed — but  its  walls  come  together  at  the  middle  part  while 
chinks  still  remain  at  the  sides.  The  blood  continues  to  pass  through 
these  chinks,  and  a  very  considerably  higher  pressure  in  the  cuff  is  re- 
quired to  obliterate  them.  That  this  is  probably  the  correct  explanation 
is  supported  by  the  observation  that,  although  in  such  patients  the  pulse 
does  not  disappear  in  the  vessels  of  the  foot  at  the  same  pressure  as  it 
does  at  the  wrist,  a  distinct  change  is  nevertheless  perceptible  in  the 
pulse  of  the  foot  at  a  cuff  pressure  equal  to  that  producing  obliteration 
in  the  wrist,  In  a  patient  showing  a  systolic  pressure  of  115  mm.  for  the 
upper  arm  and  198  mm.  for  the  leg,  at  116  mm.  the  pulse  in  the  leg, 
although  not  obliterated,  became  notably  cut  down  in  volume.  It  there- 
after persisted  at  a  small  volume  with  little  alteration  until  the  pressure 
became  sufficient  to  obliterate  it.  It  is  said  that  repeated  compression 
and  decompression  of  the  hardened  arteries  greatly  reduces  the  dis- 
crepancy in  the  systolic  readings.  Differences  in  systolic  readings  are 
also  sometimes  observed  in  normal  individuals,  particularly  after  mus- 
cular exercise,  but  for  these  no  satisfactory  explanation  can  be  given. 

While  palpating  the  radial  artery,  it  will  often  be  noticed,  as  the 
pressure  in  the  cuff  is  gradually  raised  from  zero,  that  the  force  of  the 
pulse  increases  perceptibly  until  a  pressure  of  about  50  mm.  is  reached. 
This  paradoxical  behavior  of  the  pulse  can  also  be  demonstrated  by  the 
sphygmograph  (see  page  201).  Its  cause  is  not  understood,  but  it  is 
of  significance  that  the  greatest  augmentations  occur  at  a  cuff  pressure 


132  THE    CIRCULATION    OF    THE   BLOOD 

at  which  a  sound  first  comes  to  be  heard  by  listening  over  the  artery 
at  the  elbow. 

"With  regard  to  the  diastolic  pressure,  there  has  been  some  controversy 
as  to  whether  it  is  more  accurately  gauged  by  the  oscillatory  or  the  aus- 
cultatory method.  If  both  methods  are  employed  it  will  usually  be  found 
that  the  oscillatory  gives  a  higher  reading  than  the  auscultatory.  The 
concensus  of  opinion  seems  to  be  that  the  latter  method  is  the  more  accu- 
rate, and  certainly  it  is  the  easier  to  apply,  for  with  the  oscillatory 
there  is  often  great  difficulty  in  deciding  just  exactly  when  the  maximum 
oscillation  occurs. 

The  strongest  evidence  supporting  the  conclusion  that  the  auscultatory 
readings  are  more  reliable  than  the  oscillatory  has  been  gained  by  ex- 
periments with  an  artificial  schema,  consisting  of  a  wide  glass  tube  rep- 
resenting the  armlet,  filled  with  Ringer's  solution  and  closed  by  rubber 
stoppers  pierced  by  tubes,  which  are  connected  with  a  fresh  artery,  which 
therefore  runs  from  end  to  end  inside  the  tube.  Through  tubing  connected 
with  the  artery  a  pulsatile  flow  of  oxygenated  Ringer's  solution  is  made 
to  flow  at  varying  pressures,  which  are  indicated  by  valved  manometers 
(see  page  152)  connected  with  the  artery,  tubing  just  beyond  the  com- 
pression tube.  The  pressure  in  the  latter  is  also  measured  by  a  manom- 
eter, and  it  is  caused  to  vary  by  a  suitable  compressor.  By  comparing 
the  behavior  of  the  artery  with  the  pulsating  movement  of  a  spring 
manometer  connected  with  the  compression  chamber,  under  different 
degrees  of  pressure  inside  and  outside  the  artery,  it  has  been  observed 
that  the  maximal  oscillation  occurs  when  the  artery  is  actually  some- 
what flattened  between  the  pulse  beats;  that  is,  it  occurs  at  an  outside 
pressure  above  the  diastolic  pressure,  at  which  of  course  the  vessel  should 
retain  its  circular  shape.  "When  a  stethoscope  is  applied  to  the  tube  leading 
from  the  artery  just  beyond  the  compression  chamber,  in  the  above  de- 
scribed model  sounds  similar  to  those  in  the  arm  are  heard  with  each  pul- 
sation. "While  the  pressure  is  being  gradually  lowered  from  above  the  ob- 
literation point,  these  sounds  will  be  found  to  become  first  audible  as  soon 
as  a  certain  amount  of  fluid  is  forced  through  the  compressed  area  at  each 
pulse  (the  systolic  index),  and  to  become  louder  and  often  murmurish  in 
quality  as  the  decompression  is  proceeded  with,  until  a  pressure  is  reached 
at  which  they  suddenly  become  less  intense  and  change  in  character.  At 
this  moment  it  will  be  observed  by  watching  the  artery  that  the  external 
pressure  is  no  longer  capable  of  producing  any  flattening  of  the  vessel 
between  pulses.  Evidently,  therefore,  the  change  of  sound  corresponds 
exactly  to  the  diastolic  pressure. 

"With  regard  to  the  cause  of  the  sound,  it  should  be  clearly  understood 
that  it  is  the  systolic  wave  that  produces  it,  but  its  occurrence  and  its 


BLOOD    PRESSUBE  L33 

character  when  present  arc  dependenl  upon  the  intra-arterial  pressure 
existing  during  the  diastolic  phase.  The  cause  of  the  sound  lias  been 
shown  to  depend  on  the  production  of  a  water-hammer  in  the  blood  ves- 
sels below  the  compression  cuff  (Brlanger8).     By  a  water-hammer  is 

meant  the  pressure  changes  which  are  caused  by  suddenly  stopping  the 
flow  of  water  in  a  pipe.  When  a  sudden  pressure  occurs  in  vessels  with 
elastic  Avails,  these  walls  are  thrown  into  vibration  and  so  produce  a 
sound.  In  the  taking  of  blood-pressure  measurements,  as  above  de- 
scribed, when  the  pressure  in  the  cuff  is  between  systolic  and  diastolic, 
the  volume  of  the  compressed  artery  will  increase  abruptly  with  each 
heartbeat  and  thus  permit  a  considerable  volume  of  swift-flowing  blood 
to  enter  the  rest  of  the  artery  underneath  the  cuff.  When  this  quickly 
moving  column  of  blood  comes  into  contact  with  the  stationary  blood 
filling  the  uncompressed  artery  below  the  cuff,  it  will  become  immedi- 
ately checked,  and  thus  distend  the  arterial  wall  with  unusual  violence 
and  set  it  into  vibration. 


CHAPTER  XVI 

THE  FACTORS  CONCERNED  IN  MAINTAINING  THE 
BLOOD  PRESSURE 

Having  become  familiar  with  the  principles  of  the  methods  by  which 
blood-pressure  measurements  are  made,  the  next  problem  is  to  examine 
into  the  causes  which  operate  to  maintain  the  pressure.  Two  of  these 
causes  may  be  considered  as  fundamental,  since  without  them  no  such 
pressure  could  exist.  These  are:  (1)  the  pumping  action  of  the  heart, 
and  (2)  the  peripheral  resistance — that  is,  the  resistance  to  outflow  of 
blood  from  the  ends  of  the  arterial  system.  Less  essential  though  im- 
portant factors  are:  (3)  the  volume  of  blood  in  the  blood  vessels,  (4) 
the  viscidity  or  viscosity  of  the  blood,  and  (5)  the  elasticity  of  the 
walls  of  the  vessels.  We  shall  now  proceed  to  examine  the  experimental 
evidence  which  indicates  the  relative  importance  of  each  of  these  factors. 

1.  The  Pumping-  Action  of  the  Heart 

Changes  produced  in  the  mean  arterial  blood  pressure  by  alteration 
in  the  pumping  action  of  the  heart  are  most  strikingly  demonstrated  by 
observing  this  pressure  after  cutting  or  during  stimulation  of  the  vagus 
nerves.  As  will  be  explained  later  (page  217),  impulses  conveyed 
through  these  nerves  to  the  heart  make  the  beats  slower  and  weaker. 
These  impulses  are  constantly  acting  in  the  heart,  so  that  when  both 
vagus  nerves  are  cut,  the  beats  become  more  frequent  and  stronger, 
with  the  result  that  the  mean  arterial  pressure  rises  considerably.  A 
lesser  degree  of  this  effect  can  usually  be  obtained  by  cutting  the  vagus 
nerve  on  one  side  (Fig.  27).  If  now  the  peripheral  end  of  a  cut  vagus 
nerve  is  stimulated,  as  by  applying  an  electric  current  to  it.  the  heart  will 
either  stop  beating  altogether  or  become  very  much  slowed,  with  the  result 
that  the  mean  arterial  blood  pressure  will  fall,  in  the  former  case  almost  to 
zero  and  in  the  latter,  to  a  level  corresponding  to  the  degree  of  slowing 
of  the  heart   (Fig.  28). 

2.  The  Peripheral  Resistance 

To  demonstrate  the  influence  of  peripheral  resistance  on  mean  arte- 
rial blood  pressure,  the  most  striking  experiment  is  performed  by  cut- 
ting or  stimulating  the  great  splanchnic  nerve.     In  this  nerve  impulses, 

134 


I'.l.ooi)    PRESSURE 


135 


which  are  called  vasoconstrictor  because  they  constrict  the  lumen  of  the 
blood  vessels,  are  transmitted  to  the  blood  vessels  in  the  abdomen. 
The  vessels  are  under  the  constant  influence  of  these  impulses  so  that, 
when  the  nerves  that  transmit  them  are  severed,  the  vessels  dilate  and 
thus  offer  less  resistance  to  the  movement  of  blood  along  them.  The 
result  produced  on  the  mean  arterial  blood  pressure  by  cutting  the  two 
splanchnic  nerves  is  therefore  a  marked  and  sudden  fall,  which  is  im- 
mediately recovered  from  if  the  peripheral  end  of  one  of  the  cut  nerves  is 
stimulated  artificially  (Fig.  29).  In  choosing  this  experiment  to  prove  the 
relationship  between  peripheral  resistance  and  the  mean  arterial  blood 


f,yV 


♦Sri/NnAi 


^  Cu+  i-f  Vaqas 
Uq.  LVa<jUS 


m* 


Fig.    27.- — Effect    of    cutting    the    vagus    nerve    on    the    arterial    blood    pressure. 

pressure,  it  must  be  remembered  that  it  is  not  entirely  conclusive,  since 
the  results  observed  on  the  mean  arterial  blood  pressure  from  cutting 
or  stimulating  the  nerve  may  be  in  part  explained  as  due  to  variation 
in  the  total  capacity  of  the  circulation  ;  more  room  is  created  by  cutting 
the  nerves,  less  room  by  stimulating  them. 


3.  The  Amount  of  Blood  in  the  Body 

This  can  be  altered  by  hemorrhage  or  transfusion,  and  the  results 
of  such  procedures  are  of  interest  not  only  on  account  of  their  physi- 
ologic bearing,  but  also  because  of  their  great  practical  importance. 


136 


THE    CIRCULATION    OF    THE    BLOOD 


To  appreciate  the  significance  of  the  results,  it  is  important  to  bear  in 
mind  that  the  total  volume  of  the  blood  constitutes  from  5  to  7  per  cent 
of  the  weight  of  the  animal.  This  fact  has  been  determined  partly  by 
postmortem,  and  partly  by  antemortem  measurements.  In  the  post- 
mortem method,  the  total  amount  of  blood  is  determined  by  collecting  the 
blood  while  bleeding  the  animal  to  death  and  then  washing  out  the 
vessels  with  saline  solution  until  the  escaping  fluid  is  no  longer  tinged 
with  red.  The  blood  contained  in  the  saline  solution  is  estimated  by 
colorimetric  methods   (see  page  92),  and  is  added   to  that  directly  col- 


K-mt  C  OttJ.  4 Absc&Sn 


Fig.     28. — Effect     of    stimulating    the     peripheral     end     of     the     right    vagus     on     the    arterial     blood 

pressure. 

lected.  In  the  antemortem  method  some  substance  that  does  not  dif- 
fuse through  vessel  walls  or  become  quickly  destroyed  is  added  to  the 
blood.  By  determining  the  concentration  of  this  substance  in  a  speci- 
men of  blood,  the  volume  with  which  it  has  become  mixed  can  readily  be 
calculated.  Acacia  has  recently  been  found  suitable  for  this  purpose 
(Meek),  but  the  best  known  work  (of  Haldane)  was  done  by  causing  the 
animal  to  inspire  a  known  amount  of  carbon  monoxide.  This  combines 
with  the  hemoglobin  of  the  blood  (see  page  401)  to  displace  an  equal 
quantity  of  oxygen.    By  determining  the  difference  between  the  volume 


BLOOD    I'KKSKIKK 


137 


of  carbon  monoxide  in  the  Mood  before  and  following  its  administration 
we  can  calculate  with  how  much  blood  the  known  inspired  quantity  of 
carbon  monoxide  must  have  combined.  The  results  vary  somewhat  in 
different  animals;  in  the  dog,  the  blood  constitutes  about  7.7  per  cent 
of  the  body  weight,  and  in  man,  about  5  per  cent. 

The  immediate  effect  of  hemorrhage  on  the  blood  pressure  depends  on 
the  rate  of  bleeding.    If  a  large  artery,  such  as  the  femoral,  is  cut  across, 


Ti**«  •rAfrsti^A 


Fig. 


29. — Effect     of    stimulation     of    the     left     splanchnic     nerve     on     the     arterial     blood     pressure. 
Note    the    primary     and    secondary     rises. 


the  pressure  will  show  an  immediate  but  moderate  fall,  due  largely  to  the 
fact  that  we  have  suddenly  decreased  the  peripheral  resistance.  If  on 
the  other  hand  only  a  small  artery  or  a  vein  is  opened,  the  bleeding  will 
at  first  produce  no  effect  on  the  blood  pressure,  and  it  is  only  after  some 
considerable  amount  of  blood  has  been  removed  that  it  begins  to  fall  (Fig. 
30).  To  be  more  exact,  we  may  state  that  the  removal  of  5  c.c.  of  blood  per 
kilogram  of  body  weight  does  not  influence  the  blood  pressure.  The  re- 
moval of  a  second  portion  of  5  c.c.  per  kilogram  causes  the  blood  pres- 
sure to  begin  to  fall,  the  fall  of  pressure  for  each  subsequent  5  c.c.  of 


138 


THE    CIRCULATION    OF    THE    BLOOD 


blood  per  kilogram  removed  averaging  about  6  mm.  Hg,  until  after  20 
to  25  c.c.  of  blood  per  kilogram  have  been  removed,  when  a  more  rapid 
fall  in  pressure  sets  in  (Downs'*).  "When  the  pressure  reaches  the  level 
of  from  20  to  30  mm.  Hg,  the  danger  limit  is  reached,  for  there  now 
supervenes  a  train  of  symptoms  known  as  "shock,"  and  the  chances  for  the 
animal's  recovery  become  uncertain.  That  the  removal  of  the  first  por- 
tion of  blood,  if  this  removal  is  slow  enough,  does  not  influence  the  blood 
pressure,  indicates  that  some  adjustment  has  occurred  in  the  vascular 
system  to  hold  up  the  pressure  in  spite  of  the  loss  of  blood.  This  adjust- 
ment is  believed  to  consist  in  vasoconstriction. 


Time  m Sees  &. 
Abscissa 


Fig.     30. — The    effect    of    rapid    and    slow    hemorrhage    on    the    arterial    blood    pressure.       Between 
the    second    and    third    pieces    of    tracing   an    interval    of    two    minutes    elapsed. 

Recovery  from  liemorrhage  is  remarkably  rapid,  the  original  volume  of 
blood  being  restored  within  a  few  hours.  The  chances  of  recovery  de- 
pend upon  the  amount  of  blood  lost,  A  loss  equal  to  2  or  3  per  cent  of 
the  body  weight  can  almost  always  be  recovered  from  in  laboratory  ani- 
mals, and  in  the  case  of  man  there  is  reason  to  believe  that  recovery 
may  occur  after  as  much  as  3  per  cent  of  the  body  weight  has  been  lost. 
The  recovery  of  blood  pressure  is  brought  about  partly  by  a  transfer 
of  fluid  from  the  tissues  to  the  blood.  This  abstraction  causes  a  drying 
out  of  the  tissues,  which  soon  excites  an  extreme  degree  of  thirst!  The 
dilution  of  blood  by  fluid  derived  from  the  tissues  occurs  very  rapidly, 
as  can  be  shown  by  comparison  of  the  hemoglobin  content,  or  the  number 
of  blood  corpuscles,  in  samples  of  blood  removed  immediately  before 


BLOOD    PRESSURE  139 

ami  immediately  after  a  hemorrhage.  The  specific  gravity  of  the  post- 
hemorrhagic blood  is  also  decidedly  below  normal,  indicating  that  the 
diluting  fluid  contains  a  lower  concent  rat  ion  of  dissolved  substances  than 
the  blood  plasma.  The  dilution  of  the  blood  is  indeed  often  so  great  that 
hemolysis  occurs,  the  plasma  being  distinctly  tinted  red. 

Hemorrhage  also  slightly  raises  the  hydrogen-ion  concentration  of  the 
blood  plasma,  and  diminishes  the  store  of  reserve  alkali,  so  that  the  ad- 
dition of  a  certain  amount   of  acid  to  the  blood  (e.g.,  carbon  dioxide 
causes  a  greater  rise  in  the  hydrogen-ion  concentration. 

The  deficiency  in  the  blood  elements  produced  by  the  dilution  is  recti- 
fied by  the  manufacture  of  new  corpuscles  in  the  bone  marroAV,  etc.,  but 
this  process  in  a  liberally  fed  animal  takes  several  days  for  accomplish- 
ment, and  while  it  is  going  on  microscopic  examination  of  the  blood  will 
reveal  the  presence  of  immature  corpuscles. 

Careful  studies  of  blood  regeneration  folloAving  the  removal  on  two 
successive  days,  of  25  per  cent  of  the  blood,  by  Whipple  and  Hooper, 
have  shown  that  even  in  starving  animals  the  total  amount  of  hemo- 
globin (percentage  of  hemoglobin  multiplied  by  the  volume  of  blood) 
slowly  recovers.  Recovery  is  greatly  hastened  by  feeding  with  flesh  or 
even  with  gelatin.  Removal  of  the  spleen  or  the  establishment  of  a  bili- 
ary fistula  does  not  interfere  with  the  recovery. 

Incidentally  it  will  be  advantageous  to  consider  here  the  effects  of 
transfusion.  These  are  very  different  according  to  the  nature  of  the  fluid 
used  for  transfusion.  Three  transfusion  fluids  have  been  investigated: 
(1)  blood  itself,  (2)  physiologic  saline  solution  (see  page  95),  and  (3) 
physiologic  saline  solution  containing  viscid  substances  such  as  gelatin. 
The  effects  are  also  very  different  according  to  whether  the  solutions  are 
injected  into  animals  with  .normal  blood  pressure  or  into  those  whose 
blood  pressure  has  been  lowered  by  preceding  hemorrhage. 

When  blood  is  injected  into  animals  with  normal  blood  pressure,  it 
will  very  soon  cause  the  pressure  to  rise,  and  as  the  injection  is  main- 
tained the  rise  may  continue  until  the  pressure  is  perhaps  50  per  cent 
or  more  above  its  normal  level.  If  the  injection  is  long  continued,  how- 
ever, a  sudden  fall  of  pressure  occurs,  on  account  of  engorgement  of  the 
right  side  of  the  heart.  If  the  injection  is  not  pushed  so  far,  the  increased 
blood  pressure  after  being  maintained  for  a  short  time  returns  to  its  old 
level. 

Injection  of  saline  into  a  normal  animal,  if  made  slowly,  has  no  effect 
at  all  on  the  blood  pressure;  if  more  rapidly  injected,  the  pressure  will 
rise  slightly,  but  to  a  much  less  extent  than  that  observed  Avhen  blood 
itself  is  injected.  Much  larger  quantities  of  the  saline  than  of  the  blood 
can  be  tolerated  before  cardiac  embarrassment  ensues.     After  the  dis- 


140  THE    CIRCULATION    OF    THE    BLOOD 

continuance  of  the  saline  injection,  the  blood  pressure  returns  very 
rapidly  to  its  old  level.  The  most  striking  result  of  such  experiments  is 
the  enormous  volume  of  saline  solution  which  can  be  slowly  injected 
without  perceptibly  affecting  the  pressure.  The  question  is,  Where  does 
the  fluid  go?  If  the  urinary  outflow  is  examined,  a  certain  increase  will 
usually  be  observed,  but  never  by  any  means  sufficient  to  account  for 
the  disappearance  of  the  injected  saline.  If  Ave  open  the  abdominal  cav- 
ity, we  shall  find  that  a  considerable  transudation  of  the  saline  into  the 
peritoneal  cavity  has  occurred,  and  that  the  liver  is  conspicuously  edem- 
atous. A  certain  degree  of  edema  is  also  usually  evident  in  the  tissues 
of  the  extremities. 

Still  more  interesting  and  important,  from  a  practical  standpoint,  are 
the  results  obtained  by  injecting  the  above  solutions  into  the  animals 
whose  blood  pressure  has  been  lowered  by  a  previous  hemorrhage.  If 
the  blood  removed  during  the  hemorrhage  is  defibrinated  (see  page  101), 
and  then  reinjected  into  the  animal,  it  will  bring  the  blood  pressure  al- 
most but  not  quite  back  to  its  original  level,  which  will  then  be  fairly 
well  maintained.  If,  on  the  other  hand,  saline  solution  instead  of  blood 
is  injected,  the  restoration  of  blood  pressure  (with  an  amount  of  saline 
equal  to  that  of  the  removed  blood)  will  amount  to  only  about  three- 
quarters  of  the  extent  to  which  it  had  fallen.  This  partial  recovery  is, 
moreover,  maintained  for  only  a  short  time,  after  which  the  pressure 
rapidly  falls  nearly  to  the  level  to  which  it  was  reduced  by  the  hem- 
orrhage. 

These  observations  raise  two  important  practical  questions:  (1)  "Why 
is  saline  relatively  ineffective  in  the  restoration  of  pressure?  and  (2) 
Why  does  the  pressure  thus  restored  so  quickly  fall  again? 

The  answers  to  these  questions  brings  us  to  a  consideration  of  the  next 
of  the  factors  concerned  in  the  maintenance  of  the  blood  pressure, 
namely,  the  viscosity  of  the  blood. 

4.  The  Viscosity  of  the  Blood 

The  importance  of  this  factor  arises  from  the  fact  that  facility  of  flow 
in  a  tube  is  inversely  proportional  to  the  viscosity  of  the  fluid  and 
directly  proportional  to  the  driving  pressure  to  which  it  is  subjected — 
that  is,  to  the  difference  in  pressure  between  two  points  in  the  tube. 
If  therefore  the  output  of  the  heart  should  remain  constant,  but  the 
viscosity  of  the  blood  be  decreased  by  a  saline  injection,  the  facility  of 
flow  Mould  be  increased  and  the  pressure  decreased.  This  fact  can  easily 
be  shown  experimentally  in  a  model  by  causing  gum  solutions  of  various 
concentrations  to  be  driven  through  a  glass  tube  by  means  of  a  small 
piston  pump  delivering  a  constant  amount  of  fluid  into  the  tube  with 


BLOOD    PRESSURE  141 

each  movement.    Although  the  outflow  from  the  narrow  end  of  the  tube 

must  remain  constant,  the  pressure  "m  the  tubing  will  vary  in  proportion 
to  the  viscosity  of  the  gum  solution  (Bayliss5.) 

Transferring  these  results  to  an  animal  whose  blood  pressure  has  been 
lowered  by  hemorrhage,  it  has  been  found  that  if  saline  solutions  con- 
taining a  sufficient  amount  of  gum  acacia  or  gelatin  to  make  the  viscos- 
ity about  equal  to  that  of  blood,  are  injected,  the  original  level  of  blood 
pressure  is  recovered  as  well  as  it  would  be  had  blood  itself  been  in- 
jected." A  7  per  cent  solution  of  gum  acacia  almost  fulfills  these  require- 
ments, but  unfortunately  this  solution  contains  a  slightly  greater  amount 
of  calcium  than  it  is  safe  to  inject  into  an  animal.  The  excess  of  calcium 
may,  however,  be  removed  by  exactly  neutralizing  the  gum  solution  with 
sodium  hydroxide,  neutral  red  being  used  as  an  indicator.  Most  of  the 
calcium  becomes  precipitated  as  phosphate.  The  mucilage  of  the  British 
Pharmacopeia,  diluted  five  times  with  water,  makes  a  7  per  cent  solu- 
tion of  gum  acacia.  A  6  per  cent  solution  of  gelatin,  after  being  heated 
to  100°  C,  gives  a  viscosity  similar  to  that  of  blood,  but  on  account  of 
the  possible  presence  of  tetanus  spores  such  solutions  must  be  very  care- 
fully sterilized  before  injection,  and  the  process  of  sterilization  causes 
a  decrease  in  viscosity.  The  injection  of  a  quantity  of  one  of  the  above 
solutions  equal  to  that  of  blood  lost  by  a  hemorrhage  will  usually  bring 
the  blood  pressure  back  to  its  original  height  and  hold  it  there  for  an 
hour  or  so. 

Viscosity  is,  however,  not  the  only  property  of  such  solutions  upon 
which  their  desirable  effect  depends.  The  osmotic  pressure  of  the  colloids 
also  comes  into  play.  By  injecting  saline  solution  containing  a  sufficient 
amount  of  a  colloid  such  as  soluble  starch,  which  gives  it  the  correct 
viscosity  but  has  no  osmotic  pressure,  the  blood  pressure,  although  it 
temporarily  recovers  after  transfusion,  does  not  maintain  its  recovery  in 
the  same  way  as  with  solutions  containing  gum  or  gelatin.  The  difference 
between  a  starch  solution  and  one  of  gum  or  gelatin  is  that  the  former 
has  no  osmotic  pressure,  the  effect  of  which  is  developed  mainly  on  the 
excretion  of  urine,  as  can  be  shown  by  observing  the  outflow  from  the 
ureters  during  the  injection  into  animals  of  equal  quantities  of  saline 
alone  or  of  saline  containing  starch  or  gelatin  (Knowlton6.)  With  the 
first  two  fluids  diuresis  is  produced,  but  not  with  gelatinous  solutions. 
The  reason  that  the  osmotic  pressure  of  certain  colloids  prevents  passage 
of  water  from  the  blood  into  the  uriniferous  tubules  is  that  the  develop- 
ment of  this  pressure  on  the  blood  side  of  the  renal  epithelium  tends  to 
counteract  the  filtration  pressure  by  which  the  urine  is  formed  (see 
page  514.) 

Although  the  urinary  factor  will  not  in  itself  explain  the  efficiency  of 


142  THE    CIRCULATION    OF    THIC    BLOOD 

the  colloids  in  recovering  the  blood  pressure,  the  conditions  controlling 
it  reveal  the  mechanism  by  which  the  passage  of  fluid  from  the  blood 
vessels  into  the  tissues  is  prevented  when  solutions  of  correct  composi- 
tion are  injected.  Normally  the  protein  content  of  the  blood  plasma  is 
higher  than  that  of  the  tissue  lymph,  so  that  there  is  a  continual  attrac- 
tion of  water  from  the  tissues  to  the  blood — an  attraction  which  is  nor- 
mally balanced  by  filtration  going  in  the  opposite  direction.  When  the 
filtration  pressure  in  the  blood  vessels  exceeds  the  difference  existing 
between  the  osmotic  pressure  of  their  contents  and  that  of  the  tissue 
fluids,  water  will  pass  into  the  tissue  spaces.  When  the  blood  is  diluted, 
as  by  the  injection  of  saline  solution,  the  osmotic  pressure  of  the  colloids 
in  a  given  volume  becomes  lowered  and,  the  filtration  pressure  remaining 
constant,  fluid  passes  into  the  tissue  spaces.  Of  course  these  explanations 
rest  on  the  assumption  that  the  wall  of  the  blood  vessels  consists  of  a 
membrane  which  is  permeable  to  crystalloids  but  impermeable  or  nearly 
so  to  colloids. 

Another  important  property  of  the  transfused  saline  solution  to  con- 
sider is  its  hydrogen-ion  concentration.  This  value  increases  in  the  blood 
left  in  the  body  after  hemorrhage,  and  injection  of  sodium  chloride  solu- 
tion aggravates  the  acidosis;  addition  of  NaHC03  so  as  to  make  a  0.2 
M  solution  restores  the  correct  PH,  and  at  the  same  time  restores  the 
lost  buffer  influence  (Milroy7.)  These  observations  are  of  interest  in  the 
light  of  the  recent  discovery  of  Cannon  that  a  condition  of  acidosis,  as 
judged  by  the  C02-combining  power  of  the  blood,  is  present  in  shock, 
and  that  the  development  of  this  condition  can  often  be  guarded  against 
by  bicarbonate  injections. 

5.  Elasticity  of  Vessel  Walls 

The  elasticity  of  the  vessel  walls  is  essential  to  the  maintenance  of  the 
diastolic  pressure.  If  the  walls  presented  no  elasticity  but  were  rigid, 
blood  pressure  would  fall  to  zero  between  the  heartbeats.  This  fact  can 
very  readily  be  shown  by  a  simple  physical  model  consisting  of  a  pump 
to  represent  the  heart,  connected  through  a  T-piece  with  two  tubes,  one 
of  which  is  elastic,  the  other  rigid.  The  free  end  of  each  tube  is  con- 
tracted to  a  narrow  aperture  representing  the  peripheral  resistance,  and 
either  tube  may  be  shut  off  from  the  pump  by  means  of  a  stopcock  (see 
Fig.  30).  Each  tube  should  also  be  connected  with  a  mercury  manom- 
eter. If  now  the  stopcocks  are  arranged  so  that  the  fluid  passes  into 
the  rigid  tube  while  the  pump  is  in  action,  it  will  be  found  that  with 
each  stroke  of  the  pump  the  pressure  in  the  tube  rises  considerably,  but 
that  it  falls  to  zero  between  the  strokes.  If  now  the  stopcocks  are  turned 
so  that  the  flow  is  through  the  elastic  tube,  the  action  of  the  pump  being 


HI. (MM)    PRESSURE 


14)1 


meanwhile  kept  up,  it  will  be  found  that  the  pressure  between  the  strokes 

is  maintained  at  a  height  which  is  dependent  on:  (1)  the  rate  at  which 
the  pump  is  operating,  and  (2)  the  resistance  to  outflow  from  the  tube. 
The  quicker  the  action  of  the  pump  and  the  higher  the  resistance,  the 
lower  the  fall  of  pressure  between  the  beats. 

The  physical  explanation  of  this  result  is  clearly  thai  the  fluid  within 
the  elastic  tube  when  the  wave  of  pressure  travels  into  it  from  the  pump 
distends  the  Avails  of  the  tube,  so  that  when  the  pressure  from  the  pump 
ceases  to  act,  the  stretched  elastic  walls  recoil  on  the  column  of  fluid 
and  maintain  the  pressure.  We  may  say  that  the  elastic  fibers  in  the 
vessel  walls  store  up  some  of  the  systolic  pressure  and  then  transmit  it  to 
the  blood  during'  diastole. 


Fig.  31. — Diagram  of  experiment  to  show  that  the  diastolic  pressure  depends  on  the  elasticity 
of  the  vessel  wall.  The  pulse  (produced  by  compressing  the  bulb  B)  disappears  when  fluid 
flows  through  an  elastic  tube  (F)  when  there  is  resistance  (g)  to  the  outflow.  A,  basin  of 
water;  B,  bulb  syringe;  C  and  E,  stopcocks;  D,  rigid  tube;  F,  elastic  tube;  G,  bulb  fdled  with 
sponge. 


These  considerations  would  lead  us  to  expect  that  patients  with  hard- 
ened arteries  should  exhibit  a  lower  diastolic  pressure  than  normal  per- 
sons, which,  however,  is  not  usually  the  case,  since  such  patients  also 
suffer  from  an  increase  in  the  resistance  to  the  flow  of  blood  in  the  periph- 
ery. The  pressure  pulse  in  these  patients  is,  however,  very  marked. 
On  the  other  hand,  when  the  vessel  Avails  become  more  extensible  and 
elastic,  as  in  certain  cases  of  aneurism,  the  pressure  pulse  in  the  vessels 
below  the  aneurism  is  distinctly  less  than  that  observed  in  normal  ves- 
sels of  the  same  patient. 


CHAPTER  XVII 
THE  ACTION  OF  THE  HEART 

Having  studied  the  methods  for  measurement  and  the  main  factors  con- 
cerned in  the  maintenance  of  the  arterial  blood  pressure,  we  may  now  pro- 
ceed to  study  in  greater  detail  the  two  most  important  of  these ;  namely,  the 
action  of  the  heart,  and  the  peripheral  resistance. 

The  heart  action  has  to  be  studied  from  two  viewpoints,  the  physical 
and  the  physiological.  From  the  physical  viewpoint  we  have  to  study 
the  heart  as  the  pump  of  the  circulation.  We  must  see  how  it  acts  so  as 
to  raise  the  pressure  of  the  blood  within  it,  and  how  the  valves  operate 
so  as  to  direct  the  bloodflow  always  in  one  direction.  We  must  also  ex- 
plain the  causes  of  certain  secondary  physical  phenomena,  such  as  the 
heart  sounds  which  accompany  the  heart  action,  and  of  certain  secondary 
changes  in  pressure  produced  in  the  other  thoracic  viscera  by  each  heart- 
beat. From  the  physiologic  viewpoint  we  must  investigate  the  conditions 
responsible  for  the  constant  rhythmic  activity  of  the  heart  and  the  con- 
trol to  which  this  is  subjected  through  the  nervous  system. 

THE  PUMPING  ACTION  OF  THE  HEART 

When  the  heart  is  viewed  in  the  opened  thorax  of  an  animal  kept  alive 
by  artificial  respiration  and  lying  in  the  prone  position,  it  can  be  noted 
that  with  each  contraction  the  ventricles  become  smaller  and  harder,  that 
the  apex  tends  to  rise  up  a  little,  so  that  if  the  thorax  were  intact  it 
would  press  more  firmly  against  the  walls,  and  that  it  rotates  slightly 
from  left  to  right,  but  does  not  move  nearer  the  base  of  the  heart.  If 
the  auriculo ventricular  groove  is  carefully  observed,  it  will  often  be 
noted  that  it  moves  slightly  toward  the  apex  with  each  systole,  whereas 
the  base  of  the  heart  itself,  where  it  is  attached  to  the  large  vessels,  re- 
mains fixed.  The  auricles  can  often  be  seen  to  contract  and  relax  before 
the  ventricles. 

The  most  noteworthy  results  of  this  inspection  are  that  during  sys- 
tole the  apex  of  the  heart  does  not  move  toward  the  base,  but  that 
the  auriculoventricular  groove  moves  slightly  toward  the  apex.  That 
these  same  movements  occur  in  the  intact  animal  can  be  shown  by  the 
very   simple    experiment    of   pushing   two   long    steel    knitting   needles 

144 


THE   ACTION   OF    THE    1IIAKT  11.") 

through  the  thoracic  walls  into  the  heart  Avails,  one  of  them  so  placed 
that  it  pierces  the  apex  of  the  ventricle,  the  other  so  that  it  pierces  the 
base.  The  needles  then  act  as  levers  with  their  fulcra  at  the  chest  wall, 
and  if  the  movements  of  their  outer  free  ends,  produced  by  the  movements 
of  the  heart,  are  observed,  they  will  be  found  to  confirm  the  observations 
made  on  the  exposed  heart. 

More  particular  investigations  of  the  changes  occurring  in  the  shape 
of  the  heart  cavity  during  systole  and  diastole  have  been  undertaken  by 
making  measurements  of  sections  across  the  heart  in  one  or  other  of 
these  conditions.  For  such  purposes  the  heart  in  diastole  is  easily  ob- 
tained, but  for  the  heart  in  systole  it  is  necessary  to  use  the  somewhat 
artificial  means  of  injecting  the  heart  with  hot  chromic  acid  solution 
just  before  the  death  of  the  animal.  The  chromic  acid  causes  the  cardiac 
muscle  to  contract  and  maintains  it  in  this  condition.  The  outcome  of 
these  investigations  is,  however,  not  of  much  practical  importance. 

Although  it  is  now  common  knowledge  that  the  direction  of  the  flow 
of  the  blood  is  from  the  veins  to  the  arteries,  yet  it  may  be  of  interest 
to  consider  for  a  moment  the  general  principle  of  the  methods  by  which 
"William  Harvey  succeeded  in  making  this  discovery.  His  evidence  was 
partly  anatomic,  partly  experimental.  He  pointed  out  that  the  walls  of 
the  veins,  and  of  the  auricles  to  which  they  lead,  are  very  thin,  whereas 
those  of  the  arteries  and  ventricles  are  very  thick,  and  he  concluded  that 
in  the  veins  the  blood  must  flow  gently  from  the  tissues  toward  the 
heart,  to  which  the  valves  in  the  veins  direct  it,  and  that  in  the  arteries 
it  must  be  propelled  by  pulses  with  each  systole  through  the  arteries 
towards  the  tissues  by  the  contraction  of  the  walls  of  the  ventricles.  The 
experimental  support  for  this  hypothesis  he  furnished  partly  by  clamping 
the  large  vessels,  veins  and  arteries  leading  to  or  from  the  heart,  and 
observing  the  resulting  distension  or  collapse  of  the  vessel;  and  partly  by 
calculation  of  the  amount  of  blood  which  must  be  expelled  from  the 
ventricles  in  a  given  period  of  time. 

Harvey's  discoveries  concerning  the  events  of  the  cardiac  cycle  were 
not  much  added  to  until  experimental  methods  were  devised  by  which 
the  pressure  changes  occurring  in  the  various  cavities  could  be  measured 
and  compared.  Until  such  measurements  were  elaborated,  it  was  impos- 
sible to  investigate  the  mechanism  by  which  the  various  valves  between 
the  heart  cavities  and  the  vessels  connected  with  them  perform  their 
function,  or  to  describe  with  any  degree  of  accuracy  the  events  occurring 
in  the  heart  chambers  during  the  various  phases  of  the  cardiac  cycle. 
It  is  for  the  purpose  of  ascertaining  the  exact  time  relationship  of  these 
changes  that  intracardiac  pressure  curves  are  studied. 


146 


THE    CIRCULATION    OF    THE    BLOOD 


Intracardiac  Pressure  Curves 

The  earliest  method  for  taking  such  curves  consisted  in  introducing 
into  the  cardiac  chambers  and  the  blood  vessels  of  the  horse,  so-called 
cardiac  sounds.  These  consisted  of  a  more  or  less  rigid  tube  furnished  at 
one  end  with  a  little  elastic  bag  or  ampulla  and  connected  at  the  other 
with  a  tambour,  by  means  of  rubber  tubing.  One  of  these  little  bags 
was  placed  in  one  of  the  ventricles,  another  in  the  auricle  or  aorta,  the 
tube  being  inserted,  in  the  former  case  through  one  of  the  large  veins  at 
the  root  of  the  neck ;  in  the  latter  case  through  the  carotid  artery.  The 
intracardiac  pressure  curves  obtained  in  this  way  marked  a  great  ad- 
vance over  the  methods  that  had  previously  been  used  to  study  the  events 
of  the  cardiac  cycle,  but  they  were  so  faulty  in  comparison  with  tracings 


Fig.  32. — Diagram  of  Wiggers'  optica!  manometer.  The  wide  glass  tube  (A)  (connected 
with  the  ventricle,  etc.)  is  connected  with  a  brass  cylinder  (B)  provided  with  a  stopcock  (C), 
the  lumen  of  which  comes  in  apposition  with  a  plate  (a)  having  a  small  opening  in  it.  The 
freedom  of  communication  between  B  and  a  is  regulated  by  the  position  of  the  tap.  Above  a  is 
a  segment  capsule  (t)  3  mm.  in  diameter  and  covered  by  rubber  dam.  This  carries  a  small 
mirror  (C)  fastened  so  that  it  pivots  on  the  chord  side  of  the  capsule.  Above  the  capsule  is 
arranged  an  inclined  mirror,  from  which  a  strong  beam  of  light  is  reflected  on  to  the  mirror 
(c)  on  the  capsule.  This  beam  then  travels,  back  and  the  mirror  (£)  is  adjusted  so  that  it 
impinges  on  a  moving  photographic  plate.  The  slightest  movements  of  the  small  mirror  (C) 
are    thus    greatly    magnified. 


taken  by  more  modern  methods  that  it  is  not  worth  while  considering 
them  any  further  here. 

The  physical  errors  involved  in  the  use  of  the  older  instruments  were 
due  mainly  to  the  elastic  recoil  of  the  membranes,  etc.,  used  in  their 
construction.  A  great  improvement  in  technic  was  afforded  by  the  use 
of  the  spring  manometer  of  Hiirthle  (see  page  126),  which  was  connected 
with  one  of  the  heart  cavities  by  a  cannula  filled  before  insertion  with 
some  anticoagulant  fluid.  The  cavity  of  the  tambour  was  made  as  small 
as  possible,  and  either  left  empty  or  filled  with  the  anticoagulating  fluid. 


THE    ACTION    OF   THE    III   \i:T 


147 


A  searching  investigation  into  the  physical  principles  involved  in  tak- 
ing records  of  sudden  changes  in  pressure  by  such  instruments  has,  how- 
ever, shown  that  considerable  errors  are  incurred,  the  inertia  of  the 
moving  mass  of  fluid  in  the  tubing  and  the  necessity  of  using  levers  in 
order  to  secure  records  being  responsible  for  most  of  them  (cf.  Wig- 
gers).  Their  elimination  lias  recently  been  achieved  by  usiny;  a  so-called 
optical  manometer,  one  of  which  (Wiggers')  is  shown  in  the  accom- 
panying figure.  It  consists  of  a  wide  glass  tube  A,  connected  above  with 
a  hollow  brass  cylinder  B,  provided  with  a  stopcock  C,  the  lumen  of  which 
tapers  from  below  upward  till  it  assumes  the  same  diameter  as  an  aper- 
ture in  the  segment  capsule  b,  above  it — that  is,  a  capsule  cut  away  at  one 
end — which  is  3  mm.  in  diameter  and  covered  with  rubber  dam.  By  ad- 
justment of  this  stopcock  the  pulsations  of  the  fluid  in  A  and  B  can  be 
damped  to  a  greater  or  less  extent  before  they  are  transmitted  into  the 


Carotid 


A, 


dj  \ 


w  s. 


Fig.  ii. — Optical  records  of  intraventricular  pressure;  a-!,  auricular  systole;  b-d,  prespliygmic 
period;  d-f,  sphygmic  period;  after  /,  diastole.  Instruments  of  varying  degrees  of  sensitiveness 
were    employed    in    taking    the    curves.       (From    Wiggers.) 


segment  capsule.  A  small  piece  of  celluloid  carrying  a  tiny  mirror  rests 
on  the  rubber  dam,  being  pivoted  on  the  chord  side  of  the  capsule.  A 
mirror  is  attached  to  the  capsule  with  its  plane  so  adjusted  that  the 
image  of  a  strong  light  placed  at  some  distance  from  it  is  focused  on  the 
little  mirror  carried  by  the  celluloid.  The  ray  reflected  from  the  little 
mirror  and  again  reflected  from  the  larger  mirror  is  adjusted  so  as  to 
impinge  upon  a  moving  photographic  plane  travelling  at  a  uniform  rate 
in  a  suitably  constructed  photographic  apparatus.  By  the  use  of  such 
an  apparatus  the  chief  errors  encountered  by  the  use  of  the  older  in- 
struments are  eliminated,  because  there  is  no  moving  mass  of  fluid  and 
there  are  no  levers  to  set  up  spurious  vibrations.  Curves  secured  by 
the  use  of  this  instrument  are  shown  in  Fig.  33. 

Two  objects  must  be  kept  in  view  in  analyzing  the  curves:  (1)  Curves 
obtained  from  the  different  cavities  may  be  compared  in  order  to  de- 
termine the  exact  moment  during  the  cardiac  cycle  at  which  such  pres- 


148  THE    CIRCULATION    OF    THE    BLOOD 

sure  changes  occur  as  must  serve  to  produce  opening  or  closing  of  the 
various  valves;  and  (2)  the  contour  of  the  curves  obtained  from  each 
cavity  may  be  examined  in  order  to  find  out  exactly  how  the  pressure 
in  that  particular  cavity  is  behaving. 

Comparison  of  the  Curves 

Before  using  the  curves  for  ascertaining  the  relative  pressure  in  the 
different  cavities,  they  must  be  graduated  according  to  some  scale,  for 
it  is  clear  that  by  the  use  of  instruments  like  those  we  have  been  describ- 
ing, the  absolute  pressure  value  of  each  curve  will  vary  according  to  the 
construction  of  the  instrument  (thickness  of  membrane,  etc.),  and  in- 
deed instruments  of  varying  degrees  of  resistance  must  be  employed  in 
taking  curves  from  places  having  such  different  pressures  as  exist  in 
the  auricles  and  ventricles.  The  graduation  is,  however,  a  very  easy 
matter,  and  consists,  as  already  explained  (page  126),  in  connecting  the 
instrument  by  means  of  a  T-piece  with  a  mercury  manometer  and  a  pres- 
sure bottle  and  then  marking  on  the  tracing,  the  points  corresponding  to 
each  10,  20  or  50  millimeters  of  increase  of  pressure,  as  the  case  may  be. 

To  ascertain  the  time  relationship  between  the  opening  and  the  closing 
of  the  auriculoventricular  valve,  the  tracings  should  be  taken  from  the 
right  auricle  and  the  right  ventricle,  and  to  ascertain  the  same  with  re- 
gard to  the  semilunar  valve,  from  the  left  ventricle  and  the  aorta.* 

By  comparing  the  curves  it  is  now  an  easy  matter  to  ascertain  the 
exact  moment  at  which  the  pressure  in  the  one  cavity  comes  to  equal 
that  in  the  other.  This  moment,  read  on  the  accompanying  time  tracing, 
will  obviously  indicate  that  at  which  the  particular  valve  is  just  about  to 
open  or  close.  From  the  results  of  such  experiments,  the  curves  may  be 
superimposed  as  in  Fig.  34. 

In  the  first  place  let  us  compare  the  curves  from  the  right  auricle  and 
ventricle.  The  curves  begin  at  the  very  end  of  diastole,  and  they  show 
that  a  distinct  increase  in  pressure  is  occurring  in  both  auricle  and  ven- 
tricle and  lasting  about  0.05  second.  This  is  of  course  caused  by  auric- 
ular systole,  and  since  it  occurs  in  both  cavities,  it  indicates  that  the 
passage  between  them,  the  auriculoventricular  orifice,  must  be  open. 
The  ventricular  curve  then  suddenly  shoots  away  beyond  the  auricular 
because  of  the  onset  of  systole  in  the  ventricle,  and  the  point  at  which 
the  two  curves  begin  to  separate  indicates  the  moment  at  which  the 
auriculoventricular  valves  close.  From  this  time  on  until  ventricular 
systole  has  given  place  to  diastole,  (about  0.2  second),  the  auricle  is 

*The  connections  with  the  heart  may  be  made  by  pushing  long  cannula;  down  the  large  veins  or 
arteries,  or  in  the  case  of  the  ventricles  by  inserting  a  cannula  with  a  sharp  point  directly  through 
the  wall  of  the  ventricle. 


THE    ACTION   OF   THE   HEART 


L49 


therefore  shul  off  from  the  ventricle.  The  exact  momenl  in  diastole  at 
which  the  two  cavities  arc  again  brought  into  communication — i.e.,  the 
ventricular  valves  open — is  indicated  by  the  curves  coming  together. 

Having  thus  determined  the  exact  moments  of  opening  and  closing 
of  the  auriculoventricular  valve,  we  may  now  proceed  to  compare  the 
intraventricular  pressure  curve  with  that  taken  from  the  aorta.  After  the 
necessary  calibration  corrections,  this  curve  has  been  placed  in  Fig.  3-4 
in  its  true  relationship  to  the  ventricular  curve.  Beginning  again  at  the 
end  of  diastole,  we  find  that  the  aortic  pressure  is  very  considerably 
above  that  of  the  ventricles,  indicating  that  the  semilunar  valves  must 
be  closed;  and  it  will  be  observed  that  the  intraventricular  pressure  at 


Fig.  34. — Pressure  curves  after  being  graduated  have  been  superimposed.  The  presphygmic, 
sphygmic  and  postsphygmic  periods  of  ventricular  systole  are  shown  by  the  vertical  lines.  The 
A-V  valves  close  at  the  first  line.  The  aortic  valves  open  at  the  second  line  and  close  again  at 
the  third  line.  The  A-V  valves  open  at  the  fourth  line.  The  position  of  the  two  main  heart 
sounds   is    also    indicated. 


the  beginning  of  systole  does  not  rise  sufficiently  to  open  them  until  an 
appreciable  interval  (0.02  to  0.04  second)  after  the  closure  of  the  auric- 
uloventricular valves;  that  is  to  say,  there  is  a  period  at  the  beginning 
of  ventricular  systole  during  which  the  ventricle  is  a  closed  cavity.  It 
is  a  period  during  which  the  ventricle  by  its  contraction  is  getting  up  a 
sufficient  amount  of  pressure  in  the  fluid  contained  in  it  to  force  open 
the  semilunar  valves  against  the  resistance  of  the  pressure  in  the  aorta, 
and  it  has  been  popularly  called  "the  period  of  getting  up  steam,"  or, 
in  physiologic  language,  the  isometric,  or  the  presphygmic,  period.  We 
shall  use  the  last-mentioned  term  in  our  further  discussion  here. 


150  THE    CIRCULATION    OF    THE   BLOOD 

After  the  aortic  valves  have  been  opened,  it  will  be  observed  that  the 
pressure  in  the  ventricles  is  just  a  little  above  that  in  the  aorta,  and  that 
it  continues  so  during  the  whole  of  ventricular  systole.  When  diastole 
sets  in,  the  pressure  in  the  ventricles  quickly  falls,  and  a  point  is  soon 
reached  at  which  equality  of  pressure  in  ventricle  and  aorta  is  again 
attained.  This  corresponds  to  the  moment  of  the  closure  of  the  semi- 
lunar valves.  The  pressure  in  the  ventricle,  although  now  rapidly  fall- 
ing, takes  a  little  time  before  it  has  fallen  low  enough  to  permit  the 
auricular  valves  to  open.  Here  again,  then,  the  ventricle  is  a  closed  cavity, 
and  we  have  what  is  known  as  the  postsphygmic  period. 


CHAPTER  XVIII 

THE  PUMPING  ACTION  OF  THE  HEART  (Cont'd) 

THE  CONTOUR  OF  THE  INTRACARDIAC  CURVES 

The  Ventricular  Curve 

From  an  analysis  of  the  contour  of  each  curve,  further  interesting 
points  are  brought  to  light.  The  ventricular  curve  in  the  diagram  alluded 
to  above  (Fig.  34)  is  shown  as  having  a  flat  top  or  plateau.  By  the  use 
of  the  more  modern,  optically  recording,  instruments  it  has  been  shown 
that  this  plateau  becomes  displaced  by  a  peak  if  every  precaution  is 
taken  to  prevent  dulling  down  of  the  pressure  changes  in  the  instrument, 
as  by  opening  wide  the  stopcock  in  the  instrument  (Fig.  33).  The  peak 
is,  however,  by  no  means  a  sharp  one,  so  that  we  may  fitly  describe  the 
contour  of  the  ventricular  curve  during  the  sphygmic  period  as  consist- 
ing of  a  rising  portion,  almost  continuous  with  the  curve  during  the  pre- 
sphygmic  period,  a  summit  and  then  a  declining  portion,  which  is  usually 
slower  than  the  ascending.  The  practical  value  arising  from  a  study  of  the 
curves  lies  in  the  insight  which  they  give  us  into  the  nature  of  the  stroke 
of  the  cardiac  pump.  They  show  us  that  the  impulse  which  the  ventricle 
gives  to  the  moving  mass  of  blood  in  the  aorta  is  rather  a  sudden  than  a 
sustained  one.  The  column  of  blood  in  the  aorta  is  a  mighty  thing  to 
move,  and  it  would  appear  as  if  a  sustained  pressure  brought  to  bear  on 
it  during  the  sphygmic  period  would  be  far  more  efficient  in  bringing 
about  an  adequate  movement  of  the  blood  than  a  sudden  jerk.  In  closing 
a  heavy  gate  a  slow  sustained  pressure  is  far  more  effective  than  a  short 
push. 

It  is  further  of  interest  to  note  on  the  intraventricular  pressure  curve 
that  there  is  very  little  indication  of  any  secondary  waves  or  vibrations 
at  the  moment  during  which  the  semilunar  valves  are  opened  or  closed. 
Nevertheless,  by  close  scrutiny  it  can  usually  be  seen  that  a  slight 
change  in  the  direction  of  the  ascending  curve  is  evident  when  the  valves 
open  (see  Fig.  33),  and  similarly  that  the  moment  of  closing  is  indicated 
by  a  sharper  bend  in  the  curve.  As  a  matter  of  fact,  Wiggers  has  shown 
that  the  exact  contour  of  the  curve  during  the  sphygmic  period  depends 
partly  on  the  degree  of  sensitiveness  of  the  optical  manometer  used  and 
partly  on  the  tension  existing  in  the  ventricle  just  before  contraction. 

151 


152 


THE    CIRCULATION    OF    THE    BLOOD 


In  the  case  of  the  right  ventricle  the  contour  of  the  curve  also  depends 
on  the  degree  of  resistance  to  the  bloodflow  through  the  pulmonary 
circuit,  The  top  of  the  curve  becomes  broader  when  the  initial  tension 
is  high,  and  more  rounded  when  there  is  a  high  pulmonary  resistance. 
Another  point  of  interest  in  connection  with  the  ventricular  curve  is 
that  early  in  diastole  it  descends  below  the  line  of  zero  pressure,  indicating 
that  a  negative  or  suction  pressure  must  exist  in  the  ventricle  at  this 
time.  It  will  be  further  observed,  however,  that  this  subatmospheric 
pressure  exists  for  only  a  very  short  time.  The  auriculo ventricular 
valves  being  opened,  a  similar  negative  pressure  is  also  present  in  the 
auricular  tracing.  Were  we  to  depend  on  such  records  alone  for  evidence 
of  the  actual  existence  of  this  negative  pressure  in  the  heart,  objection 
might  be  taken  to  the  conclusion  on  the  ground  that  it  was  due  to  the 


to  manometer 


max  valve 


mm  valve 


to  heart 


Fig.  35. — Von  Frank's  maximal  and  minimal  valve,  which  is  placed  in  the  course  of  the 
tube  between  heart  and  mercury  manometer.  By  turning  the  stopcocks,  it  may  be  used  as  a 
maximum,   minimum,   or   ordinary   manometer    (central    tubes    open).      (From    Starling.) 


sudden  recoil  to  which  the  instrument  is  subjected  at  the  beginning  of 
diastole.  It  is  necessary  therefore  to  control  these  observations  by  the 
use  of  an  entirely  different  method.  This  consists  in  connecting  the 
heart  with  a  valved  mercury  manometer  (see  Fig.  35).  This  instru- 
ment does  not  of  course  record  any  sudden  changes  of  pressure  in  the 
cardiac  cavity,  but  in  obedience  to  changes  in  pressure  the  mercury  slowly 
moves  in  the  direction  in  which  the  valve  permits  it  to  move.  Such  an 
instrument,  with  the  valve  opening  towards  the  heart,  is  called  a  minimal 
manometer,  and  after  it  has  been  connected  with  the  ventricle,  it  will  le 
found  that  a  negative  pressure  of  perhaps  40  or  60  mm.  Hg  is  recorded. 
Evidently,  then,  the  negative  pressure  does  actually  exist  in  the  ventricle 
during  some  phase  of  the  cycle,  and  the  question  arises  as  to  whether  it 
is  of  importance  in  connection  with  the  pumping  action  of  the  heart.  At 
first  sight,  considering  the  heart  as  an  elastic  structure,  we  might  con- 


THE    PUMPING    action    OF   THE    lll'.AKT  153 

ceive  thai  t lie  negative  pressure  would  serve  to  suck  blood  into  the  heart, 

just  as  it  sucks  water  iii  an  ordinary  ball  syringe.  Closer  consideration 
will,  however,  show  that  this  conclusion  is  untenable,  partly  because  the 
negative  pressure  exists  in  the  ventricle  for  so  short  a  period  of  time,  and 
partly  because  it  would  have  to  operate  on  the  slowly  moving  column  of 
blood  in  the  thin-walled  veins,  with  the  result  that  it  would  cause  the  walls 
of  these  vessels  to  come  together  rather  than  produce  a  movement  of  the 
blood  contained  in  them.  The  negative  pressure  of  the  heart  can  not 
therefore  be  of  much  consequence  in  attracting  the  venous  blood  into  the 
ventricle. 

Several  factors  may  cooperate  to  produce  this  negative  pressure, 
among  them  being  the  sudden  opening  out  of  the  base  of  the  ventricles 
at  the  beginning  of  diastole,  the  elastic  recoil  of  the  tissue  which  becomes 
compressed  in  the  heart  walls  during  systole,  the  turgescence  of  the  walls 
of  the  ventricles  produced  by  the  sudden  inrush  of  blood  into  the  coro- 
nary vessels  at  the  beginning  of  diastole,  all  of  which  factors  tend  to 
cause  an  opening  out  of  the  walls  of  the  ventricles  with  a  consequent 
increase  in  the  capacity  of  their  cavities. 

The  Auricular  Curve 

Examination  of  the  intraauricular  pressure  curve  is  of  particular  in- 
terest because  of  the  relationship  which  it  has  to  a  tracing  taken  of  the 
movements  in  the  jugular  vein  at  the  root  of  the  neck  (see  page  274). 
This  jugular  pulse  curve,  as  it  is  called,  is  produced  mainly  by  the 
changes  of  pressure  occurring  in  the  auricle,  from  which  it  differs  only  in 
the  relative  height  of  the  various  waves.  By  graduating  the  intra- 
auricular pressure  curve  by  the  method  described  above,  we  can  tell 
exactly  the  magnitude  in  the  changes  of  pressure  occurring  during  each 
cardiac  cycle.  This  obviously  can  not  be  done  with  a  tracing  taken  from 
the  jugular  vein,  although  qualitatively  the  tracings  reflect  exactly  the 
changes  that  are  occurring  in  the  auricle. 

On  examining  the  auricular  pressure  curve  (consult  Figs.  34  and  97),  we 
find  that  after  the  wave  of  presystole,  which  of  course  coincides  exactly 
with  that  on  the  intraventricular  curve,  a  second  wave  occurs  culminating 
in  a  peak  almost  exactly  at  the  beginning  of  the  sphygmie  period.  The 
curve  then  rapidly  descends,  usually  indeed  below  the  line  of  zero  pres- 
sure, and  slowly  rises  throughout  the  rest  of  ventricular  systole,  until 
the  moment  of  opening  of  the  auriculoventricular  valve,  when  it  descends 
again  and  thereafter  runs  parallel  with  the  ventricular  curve.  The  let- 
ters used  to  designate  the  waves  are  the  same  as  those  employed  for 
similar  waves  shown  on  the  jugular  pulse  tracing,   and  although  the 


154  THE    CIRCULATION    OF    THE    BLOOD 

lettering  is  more  or  less  arbitrary,  Ave  must  accept  it  because  of  its  gen- 
eral usage  in  all  "work  of  this  kind. 

As  to  the  causes  of  the  waves  A  is  of  course  caused  by  auricular  systole 
or  presystole;  C,  occurring  as  it  does  at  the  beginning  of  the  period  of 
ventricular  systole,  is  caused  by  the  bulging  into  the  auricle  of  the  closed 
auriculoventricular  valve.  The  floor  of  the  auricle,  in  other  words,  at 
this  moment  becomes  somewhat  elevated  and  imparts  to  the  blood  which 
is  resting  upon  it  a  slight  wave  of  pressure,  which  is  transmitted  along 
the  veins  for  a  considerable  distance.  The  succeeding  depression  is 
marked  x,  and  the  negative  pressure  which  it  indicates  is  probably  due 
to  the  co-operation  of  three  forces,  all  tending  to  increase  the  auricular 
capacity:  (1)  the  diastole  of  the  Avails  of  the  auricle;  (2)  the  descent 
of  the  auriculoventricular  groove,  thus  tending  to  open  out  someAvhat 
the  folds  in  the  Avails  of  the  auricle;  and  (3),  probably  most  important  of 
all,  the  tendency  of  the  thin-Availed  auricles  to  become  dilated  as  a  result 
of  the  sudden  diminution  in  intrathoracic  pressure  produced  at  each  heart- 
beat by  the  discharge  of  blood  from  the  heart  and  intrathoracic  blood 
vessels  into  those  of  the  rest  of  the  body.  All  thin-walled  structures 
in  the  thoracic  cavity,  the  auricles  included,  Avill  expand  to  take  up  the 
extra  room  created  in  the  thoracic  cavity.  Similar  negative  heart  pulses, 
as  they  are  called,  can  be  observed  Avith  each  systole  in  the  lungs  and 
in  the  esophagus. 

THE  MECHANISM  OF  OPENING  AND  CLOSING  OF  THE  VALVES 

When  physical  valves  open  and  close  as  a  result  of  the  changes  in  pres- 
sure on  their  two  surfaces,  a  certain  amount  of  fluid  must  succeed  in 
passing  the  valve  flaps  before  these  become  perfectly  closed.  But  there 
is  every  reason  to  believe  that  such  is  not  the  case  in  the  heart,  the  flaps 
of  both  the  auriculoventricular  and  the  semilunar  valves  being  already 
completely  closed  before  pressure  conditions  entailing  a  possible  regur- 
gitation of  blood  through  them  become  established. 

Auriculoventricular  Valves 

During  diastole  the  flaps  of  the  auriculoventricular  valves  are  hanging 
down  into  the  ventricle  and  floating  in  a  half-open  position  in  the  blood, 
Avhich  is  meaiiAvhile  accumulating  in  the  chamber.  This  position  is  de- 
pendent upon  the  operation  of  tAVo  opposing  forces  on  the  valve  flaps: 
the  pressure  of  the  blood  floAving  from  the  auricle  on  their  upper  aspects, 
and  reflected  Avaves  of  pressure  from  the  Avails  of  the  ventricle  on  their 
under  aspects  (centripetal  reflux).  When  presystole  occurs,  the  pres- 
sure of  the  auricular  stream  momentarily  increases,  thus  slightly  dis- 
tending the  Avail  of  the  meanwhile  relaxed  ventricle  and  after  a  moment's 


THE   PUMPING    ACTION    OP    THE    HEART  155 

delay  causing  the  reflected  wave  to  become  more  pronounced.  At  the 
same  time  the  muscular  fibers  in  the  valve  flaps  (Kurschner's  fibers) 
contract  and  make  the  flaps  shorter,  the  total  effect  of  the  two  factors 
being  that  the  valve  takes  up  a  position  nearer  that  of  closure.  When 
presystole  suddenly  stops,  the  reflexed  waves  will  persist  for  an  instant 
of  time  longer  than  the  auricular  wave  which  causes  them,  because  of 
the  elastic  nature  of  the  ventricular  wall,  so  that  the  valve  flaps  close 
Avith  perfect  opposition  not  merely  at  their  edges  but  also  for  a  con- 
siderable distance  along  their  upper  surfaces. 

When  ventricular  systole  starts,  the  only  effect  of  the  high  pressure 
which  is  brought  suddenly  to  bear  on  the  under  surfaces  of  the  already 
closed  valves  is  to  cause  them  to  vibrate  and  to  bulge'  into  the  auricles, 
being  meanwhile  anchored  down  and  prevented  from  flapping  into  the 
auricle  by  the  chordae  tendineae.  Although  there  is  reason  to  believe  that 
the  musculi  papillares  to  which  these  are  attached  begin  to  contract  at  the 


Fig.    36. — Diagram    to    show    the    positions    of    the    cardiac    valves:      1,    during    diastole;    2,    during 
the    presphygmic    period;    3,    during    the    sphygmic    period. 

very  outset  of  ventricular  systole — indeed  slightly  to  precede  it  (see 
page  263),  and  thus  keep  the  chordae  taut,  yet  as  systole  continues  the 
contraction  of  these  muscles  becomes  more  and  more  pronounced,  and  the 
resulting  tightening  of  the  chordae  serves  to  draw  down  the  valve  flaps, 
so  that  progressively  larger  proportions  of  their  upper  aspects  tend  to 
become  opposed.  Meanwhile  the  auriculoventricular  orifice  is  also  be- 
coming narrowed  down  on  account  of  the  contraction  of  the  musculature 
of  the  auriculoventricular  groove. 

Semilunar  Valves 

The  mechanism  involved  in  the  operation  of  the  semilunar  valves  is 
somewhat  different.  It  has  been  shown  that,  when  fluid  is  flowing  in  a 
tube,  the  pressure  and  velocity  are  not  equal  in  the  axial  and  peripheral 
parts  of  the  stream.  In  the  axis  the  velocity  is  greater  than  in  the  layers 
of  fluid  next  to  the  walls,  but  the  pressure  is  less.     These  facts  can  be 


156 


THE    CIRCULATION    OF    THE   BLOOD 


demonstrated  by  observing  the  flow  through  a  wide  tube  of  water  in 
which  are  suspended  lycopodium  spores.  By  placing  in  the  tube  small 
bent  tubes  so  arranged  that  one  open  end  lies  near  the  periphery  and 
the  other  near  the  center,  it  can  be  seen  that  the  differences  in  pressure 
are  such  as  to  cause  the  fluid  to  flow  from  periphery  to  axis  (centripetal 
eddies). 

If  the  bent  tubes  are  used  to  study  the  conditions  of  flow  in  a  tube  which 
suddenly  becomes  wider,  it  will  be  found  that  Avhere  the  wide  portion 
starts  centripetal  eddies  are  set  up,  which  tend  to  carry  the  seeds  into 
the  axis  of  the  stream,  where  their  velocity  is  greatly  increased.  Now 
these  are  the  conditions  obtaining  at  the  beginning  of  the  large  arteries 


S.a.-D.v. 


D.a.-S.v. 


Fig.    37. — Diagram    showing    the    position    of    the    cardiac    chambers    and    valves    during    presystole 
(S.a. — D.v.)     and    during    the    sphygmic    period.       (From    Landois.) 


of  the  heart,  the  orifice  into  the  ventricles  being  constricted,  while  at 
the  sinus  valsalvae  the  vessels  are  dilated.  A  centripetal  vortex  must  be 
set  up  in  the  sinus,  tending  to  throw  the  valve  flaps  into  a  closed  posi- 
tion, which,  however  is  prevented  by  the  blood  rushing  between  them 
from  the  ventricles.  They  thus  take  up  a  mid-position  and  vibrate  in 
the  stream.  When  the  efflux  from  the  ventricle  stops  at  the  end  of  sys- 
tole, the  reflux,  lasting  for  a  moment  longer  and  being  now  unopposed, 
immediately  closes  the  valves,  in  which  position  they  are  then  maintained 
by  the  greater  pressure  on  their  upper  surfaces. 

The  position  of  the  valves  relative  to  the  events  of  the  cardiac  cycle  is 
shown  in  Figs.  36  and  37. 


THE    PUMPING    ACTION    OF   THE    EEABT  157 

THE  HEART  SOUNDS 

During  certain  phases  of  the  cycle  distinct  sounds,  the  heart  sounds, 
can  be  heard  by  applying  a  Btethoscope  to  the  thoracic  Avail.  The  first 
occurs  at  the  beginning  of  ventricular  systole  and  is  best  heard  over  the 
apex  beat;  the  second  occurs  at  the  beginning  of  diastole  and  is  heard 
besl  at  the  second  right  costal  cartilage  or  in  the  second  left  intercostal 
space.  A  third  sound,  much  less  distinct,  is  sometimes  heard  in  diastole 
a  short  time  after  the  second.  To  study  the  exact  time  relationship  of 
the  sounds  the  vibrations  which  they  set  up  can  be  recorded  graphically 
alongside  cardiac  tracings  by  means  of  a  microphone  attachment  to  the 
electrocardiograph  (see  page  259). 

Causes  of  Sounds 

It  has  been  found  that  the  first  sound  consists  of  two  distinct  elements, 
one  high  pitched  and  the  other  of  a  dull  character.  The  former  element 
is  believed  to  be  the  result  of  vibrations  set  up  in  the  flaps  of  the  auric- 
uloventrieular  valves,  and  therefore  in  the  blood  in  the  heart,  by  the 
sudden  rise  in  systolic  pressure.  The  dull  element  on  the  other  hand 
is  undoubtedly  of  muscular  origin.  The  evidence  for  these  conclusions  is 
as  follows:  (1)  When  the  auriculoventricular  valves  are  prevented  from 
closing  properly  either  by  disease  or  by  pushing  a  loop  of  wire  down  the 
large  veins,  the  high  pitched  quality  disappears,  and  nothing  but  a  rush- 
ing sound  accompanies  the  dull  bruit  produced  by  the  contracting  muscle. 
(2)  In  a  heart  that  has  been  rendered  bloodless  by  an  incision  near  the 
apex,  or  even  in  an  excised  but  still  beating  heart,  the  dull  element  of 
the  first  sound  still  continues  to  be  heard  for  a  short  time.  That  con- 
tracting muscle  produces  a  sound  is  a  well-established  fact. 

There  are,  however,  many  obscure  phenomena  connected  with  the 
causation  of  the  first  sound,  but  we  can  not  go  into  such  controversial 
matters  here.  A  close  inspection  of  the  electrophonographic  tracing 
shows  that  the  sound  starts  at  the  beginning  of  the  presphygmic  period, 
and  that  it  lasts  with  gradually  declining  variation  in  intensity  until 
well  into  the  sphygmic  period  (Fig.  38). 

The  second  sound  occurs  accurately  at  the  beginning  of  diastole  and 
can  readily  be  shown  to  be  caused  by  the  sudden  shutting  and  stretching 
of  the  semilunar  valves,  which  throws  them,  the  blood  in  contact  with 
them,  and  the  neighboring  walls  of  the  aorta  into  vibration.  Proof  of 
this  conclusion  is  furnished  by  the  following  facts:  The  second  sound 
immediately  disappears  if  the  blood  is  let  out  of  the  heart  by  opening 
the  apex,  and  it  is  replaced  by  a  rushing  "bruit"  if  the  flaps  are  pre- 
vented from  closing'  as  a  result  of  disease  or  of  hooking  them  back  by 


158  THE   CIRCULATION   OF    THE   BLOOD 

passing  a  wire  down  the  carotid  artery.  The  third  sound,  although  audi- 
ble only  in  some  individuals,  ean  nevertheless  be  shown  to  exist  by  the 
electrophonograph,  and  since  it  occurs  at  the  time  when  the  auriculo- 
ventricular  valves  open,  it  is  believed  to  depend  upon  the  sudden  inrush 
of  blood  from  auricles  to  ventricles. 

The  greatest  importance  of  the  sounds  is  in  the  clinical  diagnosis  of  val- 
vular and  other  lesions  of  the  heart.  When  a  valve  leaks,  for  example, 
the  blood  escapes  past  it  under  great  pressure,  and  is  ejected  into  a  mass 
of  blood  at  low  pressure,  these  being  conditions  which  are  well  known 
to  create  sounds  or  bruits.  By  examining  the  exact  relationship  of  such 
bruits  to  the  normal  heart  sounds,  deductions  can  be  drawn  concerning 
the  condition  of  the  various  valves. 

Record  of  Heart  Sounds 

The  heart  sounds  have  been  graphically  recorded  by  transmitting  them 
through  a  stethoscope  to  a  microphone  placed  in  circuit  with  a  string 
galvanometer  (electrophonograms).  Through  this  circuit  passes  a  cur- 
rent the  strength  of-  which  depends  on  the  resistance  offered  by  the 
microphone,  this  resistance  being  proportional  to  the  number  and  ampli- 
tude of  the  vibrations  of  the  sounds  transmitted  to  it  through  the  stetho- 
scope. There  are  several  objections  to  this  method.  One  of  these  is  de- 
pendent on  the  varying  distance  of  the  heart  from  the  chest  wall,  which 
causes  many  of  the  sound  vibrations  to  be  lost  before  they  reach  the 
stethoscope;  another,  on  adventitious  sounds  arising  from  contracting 
muscles,  the  impact  of  the  heart  against  the  chest  wall,  etc.,  and  still 
another  on  unequal  resonation  by  the  air  in  the  neighboring  portions  of 
lungs.  To  investigate  the  problem  more  thoroughly,  "Wiggers,37  using 
anesthetized  animals,  has  recorded  the  sounds  by  carefully  stitching  to 
the  heart  (exposed  through  a  small  opening  in  the  pericardium)  a  lever, 
the  end  of  which  was  attached  to  a  "transmitter"  consisting  of  a 
small  capsule  covered  with  rubber  dam.  The  transmitter  was  connected 
by  rubber  tubing  to  a  "recorder"  consisting  of  another  small  capsule  carry- 
ing on  its  membrane  (made  of  rubber  cement)  an  eccentrically  placed  small 
mirror,  on  to  which  a  beam  of  light  was  thrown.  The  movements  of  the 
beam  of  light  reflected  from  the  mirror,  and  caused  by  the  sound  vibra- 
tions, were  photographed.  Mechanical  vibrations  set  up  in  the  apparatus 
itself  were  largely  eliminated  by  a  side  opening  on  the  recorder,  and  the 
effect  of  outside  sounds  minimized  by  surrounding  the  recorder  by  a 
ventilated  glass  housing. 

Although  this  apparatus  is  not  free  from  faults  due  to  inherent  vibra- 
tion frequency  and  resonance,  the  records  secured  by  it  are  valuable  in 
showing  the  exact  relationship  of  the  sounds  to  the  events  of  the  cardiac 


THE   PUMPING    ACTION    OP    THE    HEART 


159 


cycle.  The  vibrations  from  the  two  ventricles  arc  alike,  but  differ  from 
those  taken  from  the  aorta.  The  first  ventricular  sound  consists  of  from 
five  to  thirteen  irregular  vibrations,  usually  in  three  groups,  the  first 
composed  of  two  small  vibrations,  the  middle  one  of  several  large  vibra- 
tions,   and   the   third    of   a    varying   number   of   small    vibrations.      The 


'> 


A.J 


i     f  «* 


3      J 


II  II 


I       I 


Fig.  38. — Electrophonograms  along  with  intraventricular  pressure  curves  from  three  dif- 
ferent experiments.  In  A  the  uppermost  curve  shows  the  pressure,  the  middle  one  the  sounds 
of  the  right  ventricle,  and  the  lowermost  one  those  of  the  aorta.  P  indicates  the  relative  posi- 
tion of  the  curves.  M  is  due  to  mechanical  oscillations.  S2  indicates  the  second  sound,  and 
/,  z,  3,  and  4  the  corrected  time  relations  of  the  first  sounds.  In  B,  the  pressure  and  sound 
curves  are  both  from  the  left  ventricle  (letters  same  as  in  A).  In  C,  the  aortic  and  pulmonary 
arterial  sounds   are   shown    (letters  same  as   in   A).      (From   Wiggers   and   Dean.) 

duration  of  the  sound  is  from  0.05  to  0.152  seconds,  and  the  periodicity 
from  0.004  to  0.054  per  second.     When  compared  with  an  intraventricu- 


160  THE    CIRCULATION   OF    THE   BLOOD 

lar  pressure  curve,  the  initial  vibrations  occur  0.01  second  prior  to  the  rise 
in  pressure,  the  main  vibrations  reaching  their  greatest  amplitude  before 
the  sphygmic  period  begins,  and  the  final  vibrations  occurring  during 
the  early  part  of  the  sphygmic  period  and  therefore  just  before  the  aortic 
pressure  has  reached  its  height.  The  main  vibrations  therefore  occur 
during  the  descending  limb  of  the  B  wave  of  the  electrocardiogram  (be- 
ginning 0.01  second  before  its  completion),  the  small  preliminary  vibra- 
tions occurring  during  the  ascending  limb.  When  taken  from  the  aorta, 
the  record  of  the  first  sound  is  somewhat  different,  there  being  no  initial 
vibrations  and  the  main  ones  being  of  greater  frequency  and  reaching 
their  maximum  earlier  than  those  taken  from  the  ventricle.  The  sub- 
sequent vibrations  are  also  larger,  especially  when  the  aortic  pressure 
is  high  (Fig.  38). 

The  record  of  the  second  sound  at  the  ventricle  is  much  simpler  and 
usually  of  less  amplitude  than  the  first,  consisting  of  two  to  six  vibrations 
lasting  0.015  to  0.056  second.  They  begin  a  short  time  after  the  ventricu- 
lar pressure  begins  to  fall,  approximately  at  the  dicrotic  notch  of  the  aortic 
curve,  being  completed  in  from  0.015  to  0.025  second  after  the  bottom 
of  the  notch.  Their  relationship  to  the  T  wave  is  variable.  Taken  from 
the  aorta,  the  record  of  the  second  sound  shows  vibrations  of  greater 
amplitude  and  of  a  greater  frequency  than  that  from  the  ventricle. 


CHAPTER  XIX 
THE  NUTRITION  OF  THE  HEART 

THE  BLOOD  SUPPLY 

In  cold-blooded  animals,  such  as  the  frog,  the  heart  muscle  is  nourished 
by  blood  soaking  into  it  from  the  heart  chambers,  which  indeed  do  not 
form  definite  cavities  as  in  the  mammalian  heart,  but  exist  as  an  inter- 
lacement of  muscular  tissue.  In  the  hearts  of  higher  animals,  the  muscu- 
lature is  supplied  by  special  arteries  (the  coronary),  although  a  certain 
amount  of  blood  may  still  pass  directly  from  the  cardiac  cavities  into 
the  musculature  through  the  veins  of  Thebesius. 

The  relative  importance  of  the  various  branches  of  the  coronary  artery 
in  maintaining  an  adequate  nutrition  of  the  heart  has  been  studied  by 
observing  the  effect  of  occlusion  of  one  or  more  of  them  (W.  T.  Porter9.) 
Occlusion  of  the  circumflex  branch  of  the  left  coronary  artery  caused 
arrest  of  the  heartbeat  in  about  80  per  cent. of  cases,  the  arrest  being 
usually  accompanied  by  fibrillary  contraction.  Occlusion  of  the  right, 
coronary  arrested  the  ventricular  contraction  in  about  20  per  cent  of 
the  cases.  Smaller  branches  may  be  occluded  without  any  evident 
change  in  the  heartbeat. 

These  results  indicate  that  the  capillary  areas  supplied  by  the  branches 
of  the  coronary  artery  do  not  freely  anastomose  with  one  another.  They 
are  more  or  less  terminal  arteries ;  that  is,  each  branch  supplies  a  distinct 
region  of  the  cardiac  muscle.  If  one  of  the  smaller  branches  of  the  coro- 
nary is  occluded,  although  there  is  no  immediate  stoppage  of  the  heart- 
beat, yet  after  some  time  the  area  supplied  by  that  branch  usually  under- 
goes necrosis,  again  indicating  that  collateral  circulation  can  not  have 
become  established.  It  is  interesting,  however,  to  note  in  this  connection 
that  anatomic  studies  have  shown  that  a  certain  amount  of  anastomosis 
does  occur  between  capillaries  of  different  branches,  although  it  is  evi- 
dent, from  the  above  observations,  that  no  adequate  collateral  circulation 
becomes  established  through. this  anastomosis. 

PERFUSION  OF  HEART  OUTSIDE  THE  BODY 

In  order  that  the  blood  supply  through  the  coronary  arteries  may 
adequately  maintain  the  normal  nutrition  of  the  cardiac  muscle,  certain 


i62  THE    CIRCULATION   OF    THE   BLOOD 

conditions  must  be  fulfilled.  The  recognition  of  these  conditions  has 
been  accomplished  by  observations  on  the  excised  heart,  for  it  has  been 
found  that  if  they  are  fulfilled  the  mammalian  heart  can  be  made  to  beat 
in  perfectly  normal  fashion  for  several  hours  after  its  removal  from 
the  animal's  body.  Indeed  certain  mammalian  hearts,  such  as  that  of  the 
rabbit,  may  be  made  to  beat  for  several  days  outside  the  body.  We  may 
consider  the  essential  conditions  of  the  blood  supply  under  four  headings: 
(1)  the  temperature;  (2)  the  oxygen  supply;  (3)  the  pressure;  and  (4) 
the  chemical  composition.  Successful  perfusion  may  be  performed  with 
artificial  saline  solutions  (e.  g.,  Locke's),  but  it  is  simplest  in  investigating 
the  relative  importance  of  the  above  conditions  to  start  the  heart  per- 
fusion with  defibrinated  blood. 

After  bleeding  an  anesthetized  animal,  such  as  a  dog  or  a  cat,  until 
no  more  blood  can  be  removed,  the  blood  is  defibrinated  and  filtered 
through  gauze  to  remove  the  fibrin.  The  thorax  of  the  dead  animal  is 
then  quickly  opened,  ligatures  placed  around  the  main  arteries  springing 
from  the  arch  of  the  aorta,  a  cannula  with  its  end  pointing  toward  the 
heart  inserted  into  the  descending  thoracic  aorta,  and  the  latter  cut 
across  below  the  point  of  insertion  of  the  cannula.  The  heart  is  then 
quickly  removed  from  the  thorax  and  an  artificial  saline  solution 
(Locke's)  allowed  to  run  into  the  aortic  cannula  through  a  side  tube, 
until  all  the  blood  has  been  washed  out  from  the  coronary  vessels.  Dur- 
ing this  operation  the  heart  may  develop  a  few  beats  even  though  the 
solution  is  quite  cool.  The  aortic  cannula  is  now  connected  with  a  bottle 
containing  the  defibrinated  blood  diluted  with  Locke's  solution  and 
brought  to  body  temperature  by  immersion  in  a  water-bath.  By  means 
of  a  suitably  regulated  air  pressure  exerted  on  the  surface  of  the  diluted 
blood  in  the  bottle,  this  is  forced  through  an  outlet  at  the  foot  of  the 
bottle  into  tubing  which  runs  to  the  aortic  cannula.  The  fluid  thus  finds 
its  way  into  the  coronary  vessels;  for  in  passing  toward  the  heart  in  the 
aorta  it  will  close  the  semilunar  valves  and  force  its  way  under  pressure 
into  the  coronary  vessels,  subsequently  escaping  by  the  coronary  sinus  into  • 
the  right  auricle.  Very  soon  after  the  perfusion  is  started  the  heart 
begins  to  beat  vigorously  and  regularly,  thus  offering  a  suitable  prepara- 
tion upon  which  to  test  the  first  three  mentioned  conditions  necessary 
for  the  nutrition  of  the  cardiac  musculature  (Fig.  39). 

If  the  temperature  of  the  solution  is  allowed  to  fall  considerably,  the 
beat  becomes  much  slower,  and  if  the  cooling  is  proceeded  with,  the  heart 
will  after  a  while  cease  beating  altogether.  If  the  pressure  is  lowered, 
the  beat  will  not  necessarily  become  slower  but  very  much  feebler,  and 
will  soon  cease.  In  general  it  may  be  said  that  the  temperature  of  the 
solution  affects  the  rate  of  the  beat,  and  the  pressure  affects  its  strength. 


THE    NUTRITION    <>F   THE    HEART 


1G3 


Funnel  (refilling 
&  air  vent) 


StocK  solution 
{Diluted  blood + 
a  salt  solution) 

Metal  pan 
Hot  water  bath 


Fig.  39. — One  form  of  apparatus  for  recording  tracings  from  an  excised  heart  (Langendorff 
method).  The  heart  is  kept  warm  by  a  water  bath  (heart  warmer),  and  the  perfusion  fluid  is 
also    warmed.      The    driving   pressure    in    this    apparatus    is    supplied    by    gravity.      (From   Jackson.) 


Ifi4  THE    CIRCULATION    OF    THE    BLOOD 

It  is,  however,  obvious  that  in  perfused  preparations  changes  in  pres- 
sure are  likely  to  cause  alterations  in  rate  as  well  as  in  force,  unless 
great  care  is  taken  to  keep  the  heart  itself  as  warm  as  the  perfusion 
fluid. 

The  importance  of  an  adequate  pressure  in  the  coronary  vessels  has 
been  clearly  brought  out  in  certain  experiments  in  which  the  heat  has 
been  maintained  for  a  short  time  by  establishing  a  pressure  in  the  cor- 
onary vessels  by  means  of  indifferent  fluids  or  gases.  Thus,  if  oxygen 
gas  is  allowed  to  pass  through  the  vessels  under  pressure,  the  heart  will 
beat  for  a  short  time,  and  the  same  result  has  been  observed  even  Avhen 
mineral  oil  or  mercury  has  been  perfused  under  pressure  (Sollmann). 

The  necessity  for  an  adequate  oxygen  supply  is  very  readily  demon- 
strated. Tf  the  darker  blood  ejected  from  the  right  auricle  Avith  each 
heartbeat  is  transferred  immediately  to  the  perfusion  bottle,  the  heart- 
beat will  soon  become  feeble  and  irregular,  to  be  readily  restored  to 
normal  when   this   dark   blood   is  shaken   up   with   ait-   or   oxygen. 

By  artificial  perfusion  in  the  manner  above  described,  the  automatism 
of  the  heart  may  be  restored  many  hours  after  death.  Partial  restora- 
tion, confined  to  the  auricles  or  to  that  part  of  the  ventricles  lying  im- 
mediately adjacent  to  the  large  blood  vessels,  "can  also  be  accomplished 
in  the  heart  of  man  several  days  after  death,  provided  death  has  not 
been  caused  by  some  acute  toxic  infection  such  as  diphtheria  or  septice- 
mia. The  Russian  physiologist  Kuliabko,  has  succeeded  in  restoring  for 
over  an  hour  the  normal  beat  of  the  heart  of  a  three-months-old  boy 
twenty  hours  after  death  from  double  pneumonia,  but  here  again  the 
pulsation  returns  only  in  certain  parts  of  the  heart.  As  will  be  pointed 
out,  the  remarkable  resistance  of  the  heart  muscle  displayed  in  these 
experiments  has  been  taken  as  an  argument  in  favor  of  the  myogenic, 
hypothesis  for  automatic  rhythmic  power  of  cardiac  muscle,  the  argu- 
ment being  that  nervous  structures  could  not  live  so  long  a  time  after 
death.     The  fallacies  in  this  argument  are  discussed  elsewhere. 

RESUSCITATION  OF  THE  HEART  IN  SITU 

A  suitable  intracoronary  pressure  is  a  sine  qua  non  for  the  mainte- 
nance of  the  heartbeat,  and  this  is  a  fact  of  great  clinical  significance, 
for  it  indicates  that  any  attempts  to  resuscitate  a  dead  animal  are  cer- 
tain of  failure  unless  the  method  is  such  as  will  bring  a  nutrient  fluid 
under  a  certain  pressure  to  bear  on  the  coronary  arteries.  Injection  of 
fluid,  even  of  defibrinated  blood,  into  a  vein  will  obviously  fail  to  ful- 
fill this  condition,  for  the  perfusion  must  be  made  into  an  artery  so  that 
the  fluid  is  carried  down  the  aorta  and  thence  into  the  coronary  arteries. 


THE   N I  TKITIOX    OF   THE    HEART  165 

The  practical  question,  In  so  far  as  resuscitation  of  the  heartbeat  is 
concerned,  is  therefore.  How  can  u-<  get  tht  necessary  fluid  under  pres- 
sun  into  ihi'  beginning  of  tin  aortaf  EveD  if  we  were  to  transfuse  fluid 
under  considerable  pressure  into  the  aorta  through  the  carotid  artery, 

it  would  mainly  follow  the  large  vessels  leading  away  from  the  heart, 
only  a  fraction  of  it  reaching  the  beginning  of  the  aorta.  To  compel  the 
fluid  to  pass  towards  the  heart  we  must  introduce  some  obstruction  to 
its  passage  peripherally.  This  can  be  done  by  the  injection  of  a  consid- 
erable dose  of  epinephrine  (adrenaline)  in  normal  saline  solution  through 
the  needle  of  a  hypodermic  syringe  inserted  into  the  tubing  leading 
from  the  burette  or  pressure  bottle  to  the  cannula  in  the  carotid  artery. 
As  the  perfusion  fluid  is  running  in,  the  epinephrine  injection  is  quickly 
made,  artificial  respiration  and  cardiac  massage  being  meanwhile  prac- 
ticed. In  the  majority  of  animals  it  will  be  found  that  complete  res- 
toration of  the  normal  blood  pressure  can  be  effected  by  this  method. 
Indeed  by  performing  the  resuscitation  under  aseptic  conditions,  some 
animals  may  be  permanently  resuscitated  so  far  as  the  circulation  is 
concerned,  although  the  nervous  structures,  even  after  a  few  minutes 
of  "death."  never  reacquire  their  normal  condition. 

The  epinephrine  acts  mainly  by  constricting  the  small  arterioles  and 
thus  directing  the  bloodflow  towards  the  heart,  but  partly  also  by  a  direct 
stimulating  action  on  the  cardiac  muscle.  It  does  not,  however,  con- 
tract the  coronary  vessels;  on  the  contrary,  it  is  said  to  cause  these 
slightly  to  dilate. 

THE  RELATIVE  IMPORTANCE  OF  THE  VARIOUS  CONSTITUENTS 
OF  THE  PERFUSION  FLUID 

We  can  study  the  chemical  conditions  necessary  for  resuscitation 
of  the  heartbeat  by  observing  the  beat  of  an  artificially  perfused  heart 
while  solutions  of  different  chemical  composition  are  being  perfused 
through  the  coronary  vessels.  At  the  outset  we  are  impressed  with  the 
fact  that  for  successful  resuscitation  the  organic  constituents  of  the 
nutrient  fluid  are  of  trivial  importance  compared  with  the  inorganic 
constituents.  With  a  solution  containing  the  proper  proportion  of  in- 
organic salts,  and  of  course  an  adequate  supply  of  oxygen,  the  heart 
of  a  rabbit,  for  example,  may  be  made  to  continue  beating  for  several 
days.  It  is  true  that  it  will  beat  longer  if  some  of  the  organic  con- 
stituents of  the  blood  plasma,  particularly  carbohydrate,  are  present, 
but  on  the  inorganic  constituents  alone  its  ability  to  beat  is  truly 
remarkable. 


166  THE    CIRCULATION    OF   THE   BLOOD 

Observations  on  Cold-Blooded  Heart 

The  earlier  experiments  for  the  investigation  of  the  chemical  condi- 
tions necessary  for  the  maintenance  of  the  heartbeat  were  performed 
on  the  heart  of  the  frog  or  turtle.  By  perfusing  either  of  these  hearts 
with  physiologic  sodium-chloride  solution,  it  was  observed  that  though 
the  beat  might  continue  for  some  time,  yet  it  gradually  grew  feebler 
and  feebler,  until  at  last  it  ceased  altogether  with  the  heart  muscle 
in  a  condition  of  extreme  relaxation  or  diastole.  If  small  proportions 
of  potassium  and  calcium  salts  (as  chloride)  were  added  to  the  sodium- 
chloride  solution,  the  beat  was  much  better  maintained.  Doctor  Sidney 
Ringer  proved  that  the  optimum  concentration  to  produce  efficient  and 
prolonged  contraction  for  the  heart  of  the  frog  or  terrapin  is  as  follows: 
potassium  chloride,  0.03  per  cent;  calcium  chloride,  0.025  per  cent. 
The  effectiveness  of  the  solution  was  also  found  to  be  increased  by  the 
addition  of  0.003  per  cent  of  sodium  bicarbonate.  This  acts  as  a  buf- 
fer substance  (page  36),  holding  the  hydrogen-ion  concentration  at  a 
constant  level.  More  recent  work  has  shown  that  the  hydrogen-ion  con- 
centration of  the  perfusion  solutions  is  of  considerable  importance  in 
determining  the  efficiency  of  the  beat,  but  the  optimum  is  not  the  same 
for  the  hearts  of  different  kinds  of  animal,  and  indeed  it  may  differ 
for  different  parts  of  the  same  heart. 

The  question  naturally  arises  as  to  the  relative  importance  of  each 
of  the  above  salts ;  or  rather,  we  should  say,  cations,  since  the  anion, 
chlorine,  is  the  same  for  all  of  them.  The  function  of  the  sodium  chlo- 
ride in  the  solutions  is  twofold:  (1)  to  endow  the  solution  with  the 
proper  osmotic  pressure  (see  page  4)  ;  and  (2)  to  perform  the  special 
role  of  the  sodium  ion  in  the  origination  and  maintenance  of  the  auto- 
matic beat.  The  latter  function  of  Na  can  be  shown  by  observing  the  behav- 
ior of  strips  cut  out  from  the  ventricle  of  the  turtle  heart  and  placed 
in  solutions  of  correct  osmotic  pressure  but  containing  no  sodium  chlo- 
ride— isotonic  solutions  of  cane  sugar,  for  example.  They  soon  cease 
to  beat,  but  if  a  small  amount  of  sodium  chloride  is  added  to  the  cane 
sugar  solution,  rhythmic  contractions  return.  The  role  of  the  calcium 
ions  is  almost  entirely  a  pharmacologic  one.  If  a  strip  of  turtle  ven- 
tricle which  has  been  made  to  cease  beating  by  immersion  in  isotonic 
sugar  solution  is  placed  in  a  weak  solution  of  calcium  chloride  .before 
it  is  transferred  to  sodium  chloride  solution,  the  spontaneous  contrac- 
tions will  return  earlier  and  continue  for  a  longer  time.  On  the  other 
hand,  if  more  than  the  correct  amount  of  calcium  salt  is  present  in  the 
solution,  the  beats  will  soon  be  found  to  become  smaller  and  smaller 
in  amplitude,  because  relaxation  does  not  properly  occur  between  them, 
and  ultimately  they  will  cease  altogether  with  the  ventricle  in  a  condition 


THE   NUTRITION. OF   THE    HEART  167 

of  extreme  contraction,  called  calcium  rigor.  The  importance  of  calcium 
may  also  be  shown  by  attempting  to  perfuse  a  turtle  heart  with  blood 
serum  from  which  the  calcium  has  been  removed  by  the  addition  of 
sodium  oxalate  (which  precipitates  it  as  insoluble  calcium  oxalate).  The 
heart  soon  ceases  to  beat,  but  can  readily  be  made  to  do  so  again  by 
adding  a  slight  excess  of  calcium  chloride. 

The  potassium  ions  do  not  appeal',  like  those  of  calcium  and  sodium,  to 
be  absolutely  essential  for  the  maintenance  of  the  heartbeat;  at  least  the 
heart  of  the  turtle  will  beat  for  a  long  time  when  perfused  with  a  solu- 
tion containing  only  sodium  and  calcium  salts.  The  explanation  of  this 
result  need  not,  however,  necessarily  be  that  potassium  is  an  unessential 
constituent  of  the  perfusion  fluid,  for  it  may  well  depend  on  the  fact  that 
there  is  a  sufficient  store  of  potassium  locked  away  in  the  muscle  fiber 
to  supply  the  requirements  of  the  heart  muscle  for  this  ion  for  at  least 
as  long  as  the  beat  would  continue  under  any  circumstances.  In  any 
case,  we  know  that  potassium  has  a  profound  influence  on  the  heart- 
beat, for  when  the  proportion  of  it  in  the  perfusion  fluid  is  increased,  the 
beat  becomes  very  slow  and  the  tone  of  the  heart  is  greatly  diminished — 
that  is,  it  becomes  extremely  relaxed  between  the  beats;  and  if  the 
amount  is  further  increased,  will  very  soon  come  to  a  standstill  in  a 
greatly  dilated  or  diastolic  position. 

The  striking  antagonism  displayed  by  these  inorganic  cations  upon 
the  heartbeat  has  led  some  investigators  to  suggest  that  the  stimulus  re- 
sponsible for  the  rhythmic  activity  of  the  heart  depends  on  some  sort 
of  chemical  union  occurring  between  the  inorganic  cations  and  the  con- 
tractile substance  of  the  heart.  Union  of  calcium  with  the  contractile 
substance  will  lead  to  systole  or  contraction,  whereas  union  of  sodium 
or  potassium  will  lead  to  relaxation  or  diastole. 

Observations  on  Mammalian  Heart 

Investigation  of  the  efficiency  of  various  saline  solutions  on  the  iso- 
lated mammalian  heart  has  showrn  that  the  proportion  of  the  above  salts 
must  be  somewhat  different  from  that  used  for  the  cold-blooded  heart. 
As  might  be  expected,  the  most  efficient  proportions  are  those  present 
in  the  blood  serum  of  the  particular  animal  whose  heart  is  being  per- 
fused. Basing  his  proportions  upon  the  results  of  analyses  of  the  inor- 
ganic constituents  of  mammalian  blood  serum,  Locke  found  that  an 
inorganic  solution  of  the  following  composition  is  most  efficient:  so- 
dium chloride,  0.9  per  cent;  calcium  chloride,  0.024  per  cent;  potassium 
chloride,  0.042  per  cent;  and  sodium  bicarbonate,  0.01  to  0.03  per  cent. 
When  "Locke's  solution,"  as  it  is  called,  is  perfused,  with  oxygen  in  it, 
under  pressure  through  the  isolated  mammalian  heart  at  body  tempera- 


168  THE    CIRCULATION    OF    THE    BLOOD 

ture,  efficient  beating  can  be  maintained  for  many  hours.  More  recently 
a  solution  known  as  Tyrode's  is  commonly  used.  It  contains  a  small  amount 
of  magnesium  and  of  phosphates.  Although  undoubtedly  superior  for 
some  perfused  preparations,  such  as  the  intestine,  it  does  not  seem  to  be 
in  any  way  superior  to  Locke's  for  the  perfusion  of  the  heart.  The  bicar- 
bonates  and  phosphates  in  these  solutions  endow  them  with  a  hydrogen-ion 
concentration  near  that  of  the  blood  (slightly  on  the  alkaline  side  of 
neutrality),  and  at  the  same  time  they  act  as  buffer  substances. 

As  already  pointed  out,  the  organic  constituents  of  such  perfusion 
fluids  do  not  appear  to  be  relatively  of  nearly  so  much  importance  as 
the  inorganic.  Nevertheless  it  appears  that  a  small  percentage  (0.01 
per  cent)  of  glucose  does  materially  improve  the  nutritive  qualities  of 
the  solution,  and  it  has  moreover  been  shown  that  after  a  while  the  con- 
centration of  glucose  in  the  perfusion  fluid  distinctly  decreases.  This 
does  not  of  itself  necessarily  mean  that  the  glucose  is  actually  utilized 
by  the  heart  muscle:  it  might  be  stored  away  in  it  as  glycogen.  That 
some  consumption  of  carbohydrate  docs  however  occur  in  the  heart  has 
been  demonstrated  by  measuring  the  intake  of  oxygen  and  the  output 
of  carbon  dioxide  through  the  lungs  of  an  isolated  heart-lung  prepara- 
tion perfused  outside  the  body  with  defibrinated  blood.  By  experiments  of 
this  type  the  attempt  has  been  made  to  show  that  the  heart  of  diabetic 
animals  loses  the  power  of  burning  glucose  as  compared  with  the  hearts 
of  normal  animals.  While  the  experiments  are  very  suggestive,  the 
results  do  not  as  yet  justify  us  in  claiming  that  in  the  latter  disease  the 
power  of  burning  glucose  in  the  tissues  has  been   materially  depressed. 

The  concentration  of  hydrogen  ions  in  the  perfusion  fluid  has  an  im- 
portant influence  on  cardiac  efficiency.  We  also  know  that  the  most 
convenient  method  for  changing  the  hydrogen-ion  concentration  of  such 
fluids  is  by  altering  their  tension  of  carbon  dioxide  (see  page  354).  In 
a  heart-lung  preparation,*  such  alteration  in  carbon-dioxide  tension  can 
very  readily  be  brought  about  by  altering  the  percentage  of  this  gas  in 
the  air  with  which  the  lungs  are  ventilated.  To  measure  the  efficiency 
of  the  heartbeat  in  such  an  experiment,  it  is  convenient  to  enclose  the 
organ  in  a  cardioplethysmograph,  the  tracing  of  which  will  tell  us  the 
degree  to  which  the  heart  is  contracted  or  relaxed,  as  well  as  the  output 
of  blood  per  minute.  By  increasing  the  tension  of  carbon  dioxide,  it 
has  been  found  in  such  experiments  that  the  dilatation  of  the  ventricle 
is  encouraged,  so  that  the  heart  with  each  beat  discharges  a  larger  quan- 
tity of  blood  (Fig.  40).     When  defibrinated  blood  is  used  the  optimum 


*A   heart  lung    preparation    is    one   in    which   both    heart   and    lungs    arc   perfused    outside    the    body, 
the  vessels  being  suitably  connected  to  maintain  a  continuous  circulation. 


THE    NUTRITION    OF    THE    BEART 


169 


pressure  or  tension  « > i*  earbon  dioxide  has  been  found  to  lie  between  5 
and  LO  per  eenl  of  an  atmosphere. 

That  the  effed  of  carbon  dioxide  in  encouraging  the  relaxation  of  the 
heart  between  beats  is  dependent  upon  the  change  in  hydrogen-ion  con- 
centration of  the  perfusion  fluid  lias  been  shown  by  securing  the  same 
results  in  experiments  with  perfusion  fluids  to  which  different  quanti- 
ties of  weak  nonvolatile  acids  have  been  added.     These  observations  are 


wattmummmmmm     -„,  L ,    ■.■■wa^wi^^ 


y% 


WWiliMiiiM 


WBfiiiti 


Fig.  40. — Volume  curve  of  ventricles  of  cat  (lower  curve)  in  a  heart-lung  perfusion  prepara- 
tion. The  air  used  to  ventilate  the  lungs  was  replaced  between  the  arrows  by  a  mixture  con- 
taining 20%  CO:-  and  25%  0«.  This  caused  dilatation  of  the  ventricles  along  with  feebler  beats 
and  a  tendency  for  the  arterial  pressure  to  fall  (upper  curve).  The  after  effect  was  an  im- 
provement  of   the    beat.      (From    Starling.) 

of  practical  importance  because  of  the  light  which  they  throw  on  the 
cause  of  cardiac  failure  following  upon  conditions  in  which  there  has 
"been  excessive  removal  of  carbon  dioxide  from  the  blood,  as  in  forced 
ventilation  of  the  lungs.  Yandell  Henderson  has  suggested  that  sur- 
gical shock  may  be,  partly  at  least,  due  to  cardiac  failure  following  the 
"washing  out"  of  carbon  dioxide  from  the  blood  by  the  dyspnea  so 
often  incident  to  the  administration  of  anesthetics  in  surgical  operations. 


CHAPTER  XX 

THE  PHYSIOLOGY  OF  THE  HEARTBEAT 

THE  ORIGIN  AND  PROPAGATION  OF  THE  BEAT— THE  PHYSIO- 
LOGIC CHARACTERISTICS  OF  CARDIAC  MUSCLE 

The  origin  and  propagation  of  the  heartbeat  are  studied  on  the  excised 
heart  of  a  frog  or  turtle,  or  on  the  mammalian  heart  by  perfusing  it 
under  suitable  conditions,  which  have  already  been  described.  The  results 
obtained  on  the  cold-blooded  heart  apply  more  or  less  directly  to  the 
warm-blooded.  In  the  first  place  it  is  clear  that  the  rhythmic  contrac- 
tility of  the  heart  is  not  at  all  dependent  upon  the  central  nervous  sys- 
tem, for  if  it  were  so,  the  excised  heart  could  not  continue  beating.  This 
fact  does  not,  however,  necessarily  imply  that  the  beating  power  is  in- 
dependent of  nervous  structures,  for  in  the  heart  itself  an  extended  net- 
work of  nerve  cells  and  connecting  nerve  fibers  can  readily  be  demon- 
strated. It  might  quite  well  be  the  case  that  the  rhythmic  beat  is  de- 
pendent upon  the  transmission  to  the  muscle  fibers  of  the  heart  of 
impulses  generated  in  the  nerve  cells  and  transmitted  along  the  nerve 
fibers  of  this  local  nervous  system.  Such  is  the  neurogenic  hypothesis  of 
the  heartbeat. 

On  the  other  hand,  it  may  be  that  these  nervous  structures  are  not  at 
all  responsible  for  the  origination  of  the  beat,  but  serve  merely  as  sta- 
tions on  the  pathway  of  the  nerve  impulses,  transmitted  to  the  heart 
from  the  central  nervous  system  along  the  vagus  and  sympathetic  nerves, 
for  the  purpose  of  altering  the  rate  of  the  heartbeat  so  as  to  adjust  it 
to  the  requirements  of  blood  supply  in  the  various  parts  of  the  body.  In 
such  a  case  the  rhythmic  power  would  reside  in  the  muscular  tissues  of 
the  heart — that  is,  each  cardiac  muscular  cell  would  have  the  power, 
not  merely  like  skeletal  muscle  of  contracting  in  response  to  a  stimulus 
transmitted  to  it,  but  also  of  originating  that  stimulus  within  itself. 
This  is  the  myogenic  hypothesis.  Much  controversy  has  raged  around 
these  two  hypotheses  and  although  space  will  not  permit  a  detailed  study 
of  the  question,  it  will  be  necessary,  on  account  of  the  great  importance  of 
the  subject  from  the  physiologic  standpoint,  briefly  to  revieAV  the  main 
arguments  of  each  school  of  thought. 

There  is  no  piece  of  evidence  offered  by  the  advocates  of  either  the 
neurogenic  or  the  myogenic  hypothesis  that  can,  taken  singly,  be  con- 

170 


THE    PHYSIOLOGY   OF   THE    HEARTBEAT  171 

sidered  as  absolutely  conclusive.  Although  some  of  "the  proof's"  may 
at  first  sight  appear  to  be  conclusive,  yet  each  of  them  breaks  down  when 

subjected  to  a  closer  scrutiny.  It  is  only  after  "\ve  have  collected  all  the 
evidence  for  and  against  each  view  that  we  shall  be  in  a  position  to  come 
In  any  conclusion,  and  even  then  it  will  be  plain  that  our  conclusion  can 
be  only  tentative. 

Myogenic  Hypothesis 

Taking  first  of  all  the  evidence  in  support  of  the  myogenic  hypothesis, 
the  following  stands  out  most  prominently: 

1.  The  heart  beats  in  the  embryo  chick  before  any  nerve  cells  have 
grown  into  it,  and  not  only  this,  but  if  portions  of  heart  muscle  are  re- 
moved from  the  embryo  and  placed  in  blood  plasma,  they  will  continue 
beating  for  many  days  It  has  also  been  observed  that  cells  may  wander 
off  from  this  mass  of  cardiac  muscle  and  undergo  multiplication  and 
differentiation,  so  as  to  produce  isolated  muscle  cells  which  exhibit 
rhythmic  contractility.  The  rebuttal  on  the  part  of  the  neurogenists  of 
this  apparently  unassailable  evidence  is  to  the  effect  that,  although  em- 
bryonic muscle  cells  may  exhibit  the  power  of  rhythmic  contraction,  this 
does  not  mean  that  the  fully  developed  muscle  cells  will  necessarily  have 
such  power.  In  the  eary  stages  of  embryonic  development,  it  is  of  course 
evident  that  the  functions  which  in  the  fully  developed  animal  are  del- 
egated to  various  special  organs  and  tissues  should  be  performed  by  cells 
having  several  such  functions  in  common.  The  muscle  cells  of  the  heart, 
for  example,  may  to  start  with  be  possessed  of  a  power  not  only  of  con- 
tracting but  also  of  initiating  the  contraction.  It  may  be  that  they  are 
partly  nervous  in  character  and  that  only  later,  when  the  differentiation 
is  consummated,  does  the  power  of  rhythmic  contraction  become  dele- 
gated to  the  nervous  element  and  that  of  contraction  retained  by  the 
muscle  itself. 

2.  The  nervous  structure  in  the  heart  may  be  damaged  either  by  me- 
chanical means  or  by  drugs  without  apparently  interfering  with  the 
power  of  rhythmic  contraction;  for  example,  in  the  heart  of  large  tur- 
tles it  is  possible  to  dissect  out  a  considerable  amount  of  nervous  tissue 
without  any  disturbance  of  the  beat,  and  in  all  animals  the  administration 
of  atropine,  which  paralyzes  the  postganglionic  fibers  of  the  autonomic 
nervous  system  (see  page  226)  found  in  the  heart,  does  not  affect  it. 

3.  The  apex  of  the  ventricle  in  such  hearts  as  that  of  the  turtle  can 
be  shown,  by  careful  histologic  examination,  to  contain  no  nerve  cells, 
and  although  a  few  nerve  fibers  may  be  found,  these  are  functionless 
without  nerve  cells.  This  virtually  nerveless  piece  of  heart  muscle  can 
be  made  to  contract  rhythmically  by  perfusing  it  with  suitable  saline 


172  THE    CIKCL'LATIOX    OF    THE    BLOOD 

solution  under  pressure  and  starting  the  beating  by  application  of  elec- 
trical stimuli.  Isolated  strips  of  ventricular  muscle,  in  which  also  no 
nervous  element  can  be  demonstrated,  may  under  favorable  conditions 
be  caused  to  beat  quite  regularly  if  supplied  with  proper  nutrient  fluid. 
The  rebuttal  of  this  evidence  is  tAvofold:  In  the  first  place,  skeletal  mus- 
cle itself  under  certain  conditions,  such  as  exposure  to  solutions  con- 
taining an  excess  of  phosphate  (Biedermann's),  may  exhibit  rhythmic- 
contractility,  especially  on  cooling,  which  indicates  that  exhibition  of  rhyth- 
mic power  in  isolated  portions  of  cardiac  muscle  need  not  mean  that  under 
ordinary  conditions  such  power  is  responsible  for  the  normal  heartbeat. 
In  the  second  place,  it  is  pointed  out  that  although  Ave  can  not  reveal 
their  presence  by  present-day  histologic  methods,  this  is  not  conclusive 
evidence  that  the  heart-muscle  fiber  may  not  possess  some  nervous  struc- 
tures capable  of  functioning  as  nerve  cells. 

The  heart  even  of  mammals  can  be  made  to  continue  beating  for  sev- 
eral days  after  excision  from  the  body.  The  nerve  cells,  as  we  know  them 
in  the  central  nervous  system  at  least,  can  not,  on  the  other  hand,  be 
made  to  functionate  for  more  than  a  few  hours  after  death.  Therefore, 
it  is  argued,  the  heartbeat  in  surviving  mammalian  hearts  can  not  de- 
pend on  the  nervous  structures.  The  argument  is  hoAvever  easily  refuted: 
on  the  one  hand,  Ave  do  not  know  that  the  nerve  structures  situated 
peripherally  in  the  heart  muscles  are  of  the  same  A'iable  nature  as  those 
composing  the  central  nervous  system;  and,  on  the  other,  the  survival 
of  the  heart  may  in  itself  be  sufficient  to  maintain  around  the  nerve  cells 
embedded  in  it  a  nutrient  environment  Avhich  is  much  more  physiologic 
than  that  which  avc  can  supply  in  artificial  perfusions  of  surviATing 
nervous  tissues. 

4.  Circumstantial  but  nevertheless  strong  evidence  is  furnished  by 
the  fact  that  many  other  varieties  of  involuntary  muscle  are  endoAved 
with  rhythmic  contractility;  thus,  the  muscle  of  the  intestines,  of  the 
ureters,  of  the  bladder,  of  the  uterus,  of  the  blood  A~essels  of  certain 
animals,  and  of  the  lymph  vessels  in  the  so-called  lymph  hearts,  main- 
tain rhythmic  contractility  after  isolation  from  the  animal  body.  The 
rhythmic  poAver  seems  in  certain  of  these  cases  to  be  independent  of 
nervous  control. 

Neurogenic  Hypothesis 

In  favor  of  this  hypothesis  the  folloAving  evidence  is  offered: 
1.  The  heart  of  certain  animals — of  Limulus,  the  king-crab,  for  exam- 
ple, is  definitely  dependent   for  its  rhythmic   contractility  upon  neigh- 
boring nervous  structures.     The  heart  of  this  animal  is  a  tubular  sac- 
culated organ,  and  along  its  dorsal  surface  there  runs  longitudinally  a 


THE    PHYSIOLOGY    OP   THE    HEARTBEAT  IT.'! 

nerve  cord  containing  ganglion  cells  and  giving  off  fibers  which  proceed 
in  pari  directly  to  the  heart  and  in  part  1o  lateral  cords  (  l"'ij-r.  41).  Re- 
moval of  tins  median  nerve  cord  is  followed  by  total  abolition  of  the 

heartbeat:  the  heart  becomes  perfectly  quiescenl  like  an  unstimulated 
skeletal  nuisele.  In  appraising  the  evidence  at  its  line  value,  it  must  be 
noted  that  although  by  stimulation  of  the  nerve  fibers  contraction  of  the 

heart  can  he  produced,  the  contraction  is  like  that  of  a  skeletal  mus- 
cle— it  is  not  rhythmic;  and  moreover — and  this  is  most  important — if 
the  various  physiologic  properties  of  muscle  as  described  below  be  stud- 
ied (page  176),  it  will  be  found  that  in  all  of  them  the  quiescent  heart 
nuisele  behaves,  not  like  the  heart  muscle  of  other  animals,  but  like  that 
of  skeletal  muscle.  This  evidence,  therefore,  while  indisputably  showing 
that  the  heart  of  Limulus  depends  for  its  rhythmic  power  upon  neigh- 
boring nerve  structures,  does  not  justify  the  assumption  that  this  will 
be  the  ease  in  the  heart  of  animals  having  different  physiologic  properties. 
2.  The  disposition  of  the  nervous  structures  in  the  heart,  especially  of 
the  frog  and  turtle,  exactly  corresponds  to  the  degree  of  development  of 


Fig.  41. — Heart  and  cardiac  nerves  of  Limulus  polyphetnus.  (Carlson.)  aa,  anterior  ar- 
teries; la,  lateral  arteries;  In,  lateral  nerves,  time,  median  ganglionic  chain;  os,  ostii  or  afferent 
stomata,  each  pair  of  which  corresponds  to  one  of  the  segments  into  which  the  Limulus  heart 
is    divided. 

the  rhythmic  power  of  the  different  parts  of  the  heart ;  thus,  the  greatest 
rhythmic  power  is  manifested  by  the  sinus  and  the  least  by  the  tip  of  the 
ventricle  at  the  bulbns  arteriosus.  In  the  former  position  the  nerve 
structures  are  very  prominent;  in  the  latter,  no  nerve  cells  and  but  few 
nerve  fibers  can  be  detected.  This  proof  is,  however,  easily  assailed. 
In  the  first  place,  it  may  merely  be  a  coincidence  that  the  disposition  of 
the  nerve  structures  and  the  development  of  rhythmic  power  correspond. 
The  unequal  rhythmic  powers  may  depend  primarily  on  a  difference 
in  structure  of  the  muscle  fibers  themselves,  such  differences  having 
been  shown  to  exist  between  the  muscle  cells  of  the  sinus  and  those 
of,  say,  the  ventricle.  The  former  cells,  for  example,  have  much  less 
developed  crossed  striation  and  their  protoplasm  is  much  more  gran- 
ular; in  short,  they  are  much  more  embryonic  in  type  than  the  cells  from 
the  tip  of  the  ventricle. 

If  a  jury  had  to  return  a  verdict  from  evidence  of  so  conflicting  a  char- 
acter, it  would  no  doubt  be  equivalent  to  that  of  the  Scottish  court — "not 


174  THE    CIRCULATION    OF    THE   BLOOD 

proven."  But  it  is  likely  that  the  majority  of  the  jury  would  vote 
in  favor  of  the  myogenic  hypothesis.  Probably  the  safest  viewpoint  to 
take  at  the  present  time  is  that  the  power  of  rhythmic  contraction  is 
inherent  in  the  cardiac  muscle  fibers,  being  most  highly  developed  in 
those  of  the  venous  end  of  the  heart,  and  least  developed  in  those  of 
the  arterial  end.  Such  a  conclusion  does  not  deny  to  the  nervous  struc- 
tures of  the  heart  the  power  under  certain  conditions  of  also  assuming 
rhythmic  activity.  In  one  case  at  least — namely,  the  heart  of  Limulus — - 
we  know  that  this  is  so.  For  some  reason  in  this  animal  the  cardiac 
muscle  fiber  has  lost  its  inherent  rhythmic  power,  and  is  now  dependent 
for  its  activities  upon  rhythmic  nervous  discharges  transmitted  to  it 
from  the  neighboring  nerve  cords,  a  condition  which  is  paralleled  in 
the  higher  animals  in  the  innervation  of  the  respiratory  muscles.  The 
respiratory  center  rhythmically  discharges  impulses  to  the  muscles,  which 
are  quiescent  in  the  absence  of  these  impulses. 

The  Pacemaker  of  the  Heart  and  Heart-block 

In  a  volume  of  this  nature,  devoted  primarily  to  the  practical  appli- 
cation of  physiology,  the  discussion  of  these  problems  may  seem  a  little 
out  of  place,  but  that  this  is  not  the  case  is  seen  when  we  consider  that 
the  experiments  upon  which  the  various  points  of  evidence  depend 
bring  to  light  facts  of  the  very  greatest  importance  in  the  study  of  the 
physiology  of  the  heartbeat.  One  fact  which  stands  out  prominently 
is  that  the  greatest  rhythmic  power  resides  in  the  basal  portion  of  the 
heart — that  is,  in  what  corresponds,  in  the  more  primitive  hearts,  to  the 
sinus  venosus. 

Although  the  muscle  of  the  entire  heart  possesses  rhythmic  power,  it 
does  not  do  so  to  an  equal  degree;  in  the  sinus  the  rhythmic  power  is 
extraordinarily  developed,  while  in  the  bulbus  arteriosus  it  is  scarcely 
recognizable.  This  observation  suggests  the  possibility  that  the  sinus 
may  dominate  the  heartbeat — that  it  may  be  the  "pacemaker"  for  the 
heart  as  a  whole.  The  most  natural  method  for  demonstrating  such  a 
possibility  would  be  to  observe  the  effect  on  the  heartbeat  of  some  block 
between  the  sinus  and  the  rest  of  the  heart.  Such  a  block  can  be  intro- 
duced in  the  heart  of  cold-blooded  animals  by  local  compression  around 
the  various  junctions.  If  a  thread  is  tied  around  the  sinoauricular 
junction,  the  sinus  will  go  on  beating  uninterruptedly,  but  the  auricles 
and  ventricles — that  is,  the  greater  part  of  the  heart  below  the  ligatures 
— will  cease  beating,  sometimes  entirely  (Stannius'  ligature).  After  a 
while,  however,  the  heart  below  the  ligature  will  usually  begin  to  beat, 
but  at  a  rhythm  which  is  slower  than,  and  independent  of,  that  of  the 
sinus. 


T1IK    PHYSIOLOGY    OF   Till:    HEARTBEAT 


175 


The  experiment  can  be  still  better  performed  by  usimj;  a  wedge- 
shaped  clamp.  (Gaskell's  clamp.)  If  ihis  is  applied  so  that  the  heart 
can   be  pinched  cither  at   the  sinoaui'icular  junction  or  at  the  auriculo- 

ventricnlar,   it  will   he   found    that,    as   the   cardiac    tissue    is    gradually 


Fig.    42. — Heart-block    produced    by    applying    clamp    at    a-v    junction.       The    clamp    was    tightened 

at    a.      (From    Brubaker.) 

pinched,  the  portion  of  the  heart  below  fails  to  heat  as  quickly  as  that 
above  the  clamp  (Fig.  42).  This  is  known  as  partial  heart-block,  and 
the  degree  of  the  block  is  indicated  by  the  numerical  expression  2  to  1, 
3  to  1,  4  to  1,  etc.,  meaning  that  the  sinus  is  beating  either  twice  as 
quickly  as  the  ventricle,  or  three  times,  or  four  times  as  the  case  may 


Fig.  43. — Tracing  of  contraction  of  ventricle,  showing  the  effect  of  the  local  application 
of  heat  to  the  auricle  at  /,  and  to  the  apex  of  the  ventricle  at  2.  Note  that  the  rate  in- 
creased   in    the    former    case. 


be.     Similar  conditions  of  heart-block  may  also  be  produced  by  cutting 
the  cardiac  tissue  partly  across  at  various  places  in  the  heart. 

Further  evidence  that  the  sinus  dominates  the  beat  in  the  heart  of 


176  THE    CIRCULATION    OF    THE   BLOOD 

cold-blooded  animals  is  furnished  by  observing  the  effects  of  local  heat- 
ing  or  cooling  of  the  various  parts  of  the  heart.  In  all  rhythmically 
acting  structures  it  is  well-known  that  heat  increases  the  rate  of  the 
rhythm  and  cold  depresses  it.  If  we  locally  warm  the  region  of  the 
sinus,  as  by  holding  a  heated  wire  near  it  the  whole  heart  will  immedi- 
ately beat  quicker;  but  if  Ave  locally  heat  the  tip  of  the  ventricle,  no 
alteration  of  rhythm  will  be  observed  to  occur  (Fig.  43). 

The  establishment  of  the  fact  that  the  sinus  dominates  the  heartbeat 
— that  it  is  the  pacemaker  of  the  beat — raises  the  question  as  to  bow  the 
impulse  originated  at  this  place  is  transmitted  over  the  rest  of  the 
heart,  and  here  again  a  neurogenic  and  a  myogenic  hypothesis  have  to 
lie  considered.  Before  going  into  this  question,  however,  it  will  be  well 
tor  us  to  consider  briefly  the  manner  of  response  of  cardiac  muscle 
i'iber  to  a  stimulus,  because  the  behavior  of  cardiac  muscle  under  such 
conditions  is  considerably  different  in  many  regards  from  that  of  skel- 
etal muscle,  and  it  is  to  these  differences  that  many  of  the  peculiar 
alterations  in  the  beat  observed  after  interfering  with  the  conducting 
structures  between  the  sinus  and  the  rest  of  the  heart,  are  to  be  ex- 
plained. 

The   Physiologic   Characteristics   of   Cardiac   Muscle 

It  is  necessary  to  bring  the  heart  into  a  quiescent  state  in  order  to 
investigate  the  properties  of  its  musculature.  This  is  accomplished  by 
the  application  of  the  Stannius  ligature  between  the  sinus  and  the  auri- 


...3 


Fig.  44. — Frog  heart  showing  the  i  osition  of  the  first  and  second  ligatures  of  Stannius 
(Hedon):  1,  auricles;  2,  sinus;  3,  ventricle.  It  is  the  first  ligature  which  brings  the  heart 
to    standstill. 

cles  (Fig.  44).  After  tightening  the  ligature  the  auricles  and  ventricles 
become  quiescent,  and  by  observing  the  effects  produced  by  the  appli- 
cation of  electric  or  other,  stimuli  we  can  compare  the  behavior  of  the 
cardiac  muscle  with  that  of  skeletal  muscle  similarly  stimulated.  This 
comparison  is  made  because  of  the  assistance  which  it  offers  in  compre- 
hending the  properties  of  cardiac  muscle.  As  a  matter  of  fact,  recent 
investigations  have  shown  that  the  differences  between  the  two  types  of 
muscle  are  not  fundamental,  since  under  certain  conditions  the  one  may 


THE    PHYSIOIiOGY    OP    THE    HEARTBEAT 


177 


be  made  to  behave  like  the  oilier.    They  are  dependent  upon  ihc  pres- 
ence or  absence  of  anastomosis  between  the  muscle  fibers. 

1.  When  electric  stimuli  of  varying  strengths  are  applied  to  skeletal 
muscle,  the  contraction  produced  by  each  stimulus  is  proportional  to 
the  strength  of  the  hitler  until  this  has  become  of  such  ;i  strength  that 
the  maximal  response  is  elicited.  In  cardiac  muscle,  on  the  other  hand. 
an  entirely  different  result  is  obtained,  for  the  weakest  stimulus,  if  it 
produces  any  response  at  all.  produces  one  that  is  maximal;  that  is,  the 
height  of  contract  ion  is  the  same  as  it  would  have  been  had  a  much 
stronger  stimulus  been  applied.  Expressing  this  result  in  general  terms, 
we  may  say  that   in  cardiac,  muscle  a  minimal  stimulus  produces  ft  mari- 


A. — Skeletal    Muscle 


B. — Cardiac    Muscle 

Fig.    45. —  Effects    of    stimuli    of    increasing    strength    on    skeletal    and    cardiac    muscle    to    illustrate 
the    "all    or    nothing"    principle    in    the    latter.       i  From    Practical    Physiology.) 


mal  effect,  whereas  in  skeletal,  the  effect,  as  measured  by  the  height  of 
contraction,  is  proportional  to  the  intensity  of  stimulation.  This  is  some- 
times known  as  the  "all  or  nothing  phenomenon"  (Fig.  45). 

2.  If  maximal  stimuli  are  applied  successively  and  at  short  intervals 
of  time  to  skeletal  muscle,  a  slightly  higher  response  results  from  each 
succeeding  stimulus,  until  about  ten  stimuli  have  been  applied,  after 
which  for  some  considerable  time  the  same  height  of  contraction  follows 
each  stimulus.  If  each  contraction  is  recorded,  it  will  be  seen  that  the 
first  few  contractions  give  a  staircase  effect ;  that  is,  if  a  horizontal  line  is 
drawn  from  the  top  of  each  contraction  to  the  next  one,  the  effect  of  a 


178 


THE    CIRCULATION    OF    THE    BLOOD 


staircase  with  gradually  diminishing  steps  will  be  produced.  If  we  repeat 
this  observation  with  cardiac  muscle,  we  shall  find  that  the  staircase 
phenomenon  or  treppe,  as  it  is  called,  is  very  pronounced ;  and  moreover, 
in  obedience  to  the  all  or  nothing  principle,  the  treppe  is  obtained  in 
cardiac  muscle  whatever  may  be  the  relative  strengths  of  the  stimuli 
applied  to  the  heart,  provided  always  that  all  of  them  are  effective; 
whereas  in  the  case  of  skeletal  muscle  it  can  be  demonstrated  only  pro- 
vided the  stimuli  are  of  equal  strength  (Fig.  46). 

3.  If  an  effective  stimulus  is  applied  to  a  skeletal  muscle  while  in  process 


Skeletal    muscle 


Cardiac    muscle 

Fig.   46. — The   effects   of  successive   stimuli    on   skeletal   and   cardiac   muscle   to   show   the   prominence 
of    the    staircase    phenomenon,    or    treppe,    in    the    latter.       (From    T.    G.    Brodie.) 


of  contraction,  as  in  response  to  a  preceding  stimulus,  the  second  stimulus 
prolongs  the  contraction  produced  by  the  first  one.  If,  however,  the  second 
stimulus  is  applied  during  the  latent  period*  of  the  first  one,  it  will  have  no 
effect — that  is,  the  muscle  during  this  period  is  refractory.!  From  these 
results  it  follows  that  stimuli  succeeding  each  other  during  the  contraction 
period  will,  in  the  case  of  skeletal  muscle,  cause  a  continuous  contraction,  or 
tetanus,  as  it  is  called,  because  the  contraction  produced  by  each  stimu- 
lus will  add-  itself  to  that  of  its  predecessor  before  any  trace  of  relax- 
ation has  set  in.  If,  however,  the  second  stimulus  is  applied  so  late  in 
the  contraction  period  of  the  first  that  time  is  not  available  for  the  latent 


*By  "latent  period"  is  meant  the  period  after  the  moment  of  application  of  a  stimulus  during 
which  no  effect  of  that  stimulus  is  observed. 

tBy  "refractory  period"  is  meant  the  time  following  the  application  of  a  stimulus  during  which  a 
second  stimulus  develops  less  than  its  full  effect  or  no  effect  at  all. 


THE   PHYSIOLOGY    OF   THE    HEARTBEAT  179 

period  to  expend  itself,  then  obviously  a  slighl  relaxation  will  have  oc- 
curred  before  the  effect  of  the  second  stimulus  develops  itself,  and  tet- 
anus will   be  incomplete.     These   facts  will   he  evident  from  the  ac< I 

panying  tracings  (Fig.  47). 


Skeletal  muscle  Stannius'  heart 

FiK  47_The  effects  of  successive  stimuli  and  of  tetanizing  stimuli  on  skeletal  muscle  and 
cardiac  muscle.  The  small  vertical  marks  show  when  the  stimuli- were  introduced.  (Compiled 
from,  tracings    published    by    T.     G.    Brodie    and     Leonard    Hill.) 

In  the  case  of  cardiac  muscle  the  above  described  properties  are  quite 
different,  for  the  refractory  phase  extends  throughout  the  whole  period  of 
contraction;  that  is,  a  second  stimulus  applied  during  the  contraction 
produced  by  a  previous  stimulus  has  no  effect  whatsoever;  it  does  not 


180 


THE    CIRCULATION    OP    THE    HLOOli 


have  one  until  Hie  muscle  has  reached  the  full  extent  of  its  contraction 

and  is  about  to  relax.  Since  a  latent  period  must  supervene. upon  the 
application  of  this  second  stimulus,  it  follows  that  no  complete  fusion  of 
the  contractions  is  possible.  Complete  tetanus  therefore,  does  not  occur 
in  cardiac  muscle,  however  frequently  the  stimuli  may  be  applied  (Pig. 
47). 

The  refractory  phase  is  a  property  of  extreme  importance  in  under- 
standing many  of  the  peculiar  irregularities  observed  in  cardiac  action. 
If  we  observe  the  effect  of  stimuli  applied  at  varying  periods  after  the 


•A] 
A. 
A 
A 
■A. 
•A. 

A 

A 

0 

NAAAAf 
/YAA  A  J\P 
/YA/IAAA 
H\  AAA/ 
IvAAJUA 
A  A  AAA/ 
ZlAAAA/ 
AAAAJV 

Fig.  48. — Myograms  of  frog's  ventricle,  showing  effect  of  excitation  by  break  induction 
shocks  at  various  moments  of  the  cardiac  cycle.  The  line  O  indicates  the  commencement  of 
all  the  beats  during  which  the  shock  is  sent  in.  It  will  be  noted  that  in  /,  2  and  3,  the  heart 
is  refractory  to  the  stimulus.  The  signals  indicate  the  moments  at  which  the  stimuli  were  ap- 
plied. From  4  to  S  the  heart  reacts  by  an  extrasystole.  after  a  delay,  which  is  progressively  less 
the  later  in  diastole  the  stimulus  enters,  as  shown  by  the  sections  shaded  obliquely  to  make  them 
more  conspicuous.  The  extrasystolcs  increase  in  height  from  4  to  5,  each  being  followed  by. 
a    compensatory    pause.       (From     f.uciani's    Human    Physiology.) 


termination  of  the  refractory  phase  of  a  previous  stimulus,  we  shall  find 
that  the  height  of  the  extra  contraction  is  directly  proportional  to  the 
time  after  the  end  of  the  refractory  period  at  which  it  is  applied.  If  a 
stimulus  is  applied  at  the  very  beginning  of  diastole,  the  extra  contrac- 
tion will  be  small,  whereas  if  it  is  applied  at  the  end  of  diastole,  the 
extra  contraction  will  be  at  least  as  high  as  that  of  the  preceding.  It 
may  be  higher  because  of  the  treppe. 


THE    PHYSIOLOGY    OF   THE    HEARTBEAT  181 

These  observations  enable  us  to  interpret  the  results  obtained  by  ap- 
plying electric  shocks  {extra  stimuli*  to  the  beating  heart  during  different 

phases  of  systole  and  diastole.  During  systole,  the  muscle  being  refrac- 
tory, no  effect  is  produced,  by  the  extra  stimulus,  but  during  diastole 
extra  systoles  which  are  progressively  more  pronounced  the  later  in 
diastole  they  occur,  follow  the  application  of  each  stimulus.  These  re- 
sults are  so  far  exactly  like  those  obtained  with  a  quiescent  heart.  But 
another  phenomenon  now  becomes  evident;  namely,  that  following  each 
extra  systole  there  is  a  compensatory  pause  in  the  action  of  the  heart, 
of  such  duration  that,  -when  the  next  natural  beat  occurs,  it  does  so 
practically  at  the  same  time  as  it  would  have  occurred  had  no  artificial 
stimulus  been  applied.  This  will  be  apparent  from  the  following  dia- 
gram (Fig.  48). 

It  should  be  noted  that  the  refractory  period  is  greatly  diminished  by 
raising  the  temperature  of  the  heart.  Indeed,  under  these  conditions 
and  with  strong  stimulation  it  may  be  possible  to  produce  an  almost 
eomplete  tetanus. 

The  importance  of  knowing  the  above  facts  is  that  we  are  thereby 
enabled  to  explain  the  peculiar  manner  in  which  the  ventricle  responds 
to  stimuli  transmitted  to  it  from  the  sinus  and  the  auricle.  The  muscu- 
lature of  the  auricle  and  ventricle  of  the  mammalian  heart  is  not  one 
continuous  sheet,  but  is  separated  by  a  space  at  the  auriculoventricular 
junction,  across  which,  in  specially  organized  structures,  the  beat  of  the 
auricle  is  transmitted  to  the  ventricle.  Sometimes  the  stimuli  are  so 
frequent  that  the  ventricular  muscle  is  unable  to  respond  to  each  stimu- 
lus transmitted  to  it,  with  the  result  that  marked  irregularities  in  con- 
traction occur  (see  page  280).  In  this  way  certain  of  the  cardiac  irregu- 
larities observed  in  man  can  be  explained.  Thus,  the  so-called  pulsus 
bigeminus  is  due  to  every  second  beat  being  an  extra  systole.  This  second 
beat  is  therefore  generally  weaker  than  the  preceding  and  succeeding  nor- 
mal beats,  and  it  is  almost  always  followed  by  a  compensatory  pause.  When 
the  intervals  separating  the  beats  are  of  uniform  length,  although  every 
second  beat  is  diminished  in  size,  the  pulse  is  termed  jyulsus  alternans. 


CHAPTER  XXI 

THE  PHYSIOLOGY  OF  THE  HEARTBEAT  (Cont'd) 

THE  ORIGIN  AND  PROPAGATION  OF  THE  BEAT  IN  THE 
MAMMALIAN  HEART 

As  has  been  shown  in  the  preceding  chapter,  there  is  no  doubt  that 
in  the  cold-blooded  heart  the  beat  originates  at  the  sinus  venosus,  whence 
it  spreads  to  the  rest  of  the  heart.  Very  strong  evidence  has  also  been 
presented  to  indicate  that  the  beating  power  is  inherent  in  the  muscle 
fiber  itself  and  independent  of  nervous  structure.  This  would  suggest  the 
further  possibility  that  the  structures  through  which  the  beat  is  propa- 
gated are  the  muscle  fibers  and  not  the  nerve  fibers^— in  other  words, 
that  the  propagation  of  the  heartbeat,  like  its  origination,  is  myogenic 
rather  than  neurogenic.  Direct  proof  of  this  hypothesis  is  readily  fur- 
nished by  numerous  experiments,  among  which  may  be  mentioned  mak- 
ing interdigitating  cuts  across  the  heart,  or  excising  a  ribbon  of  ven- 
tricular muscle  by  an  incision  simulating  the  walls  of  Troy.  In  both 
these  cases  the  beat  will  be  found  to  travel  from  one  end  of  the  muscular 
band  to  the  other,  although  it  is  evident  that  all  the  nerves  proceeding 
from  base  to  apex  of  the  heart  must  have  been  severed.  Of  course  this 
evidence  is  not  irrefutable,  for  it  might  be  argued  that  there  are  nerv- 
ous structures  disposed  in  the  form  of  a  plexus  continuously  all  over  the 
heart,  and  that  some  branches  of  the  plexus  remain  uncut  in  the  above 
experiments.  It  is  only  in  the  heart  of  Limulus  that  undoubted  evidence 
exists  that  the  beat  is  transmitted  by  nerves,  but  as  Ave  have  seen,  this 
heart  in  all  its  properties  is  probably  the  proverbial  exception  which 
proves  the  rule.  The  balance  of  evidence  stands  in  favor  of  the  view 
that  the  propagation  of  the  beat  over  the  cold-blooded  heart  is  myogenic 
and  not  neurogenic. 

CONDUCTING  TISSUE  IN  MAMMALIAN  HEART 

When  we  attempt  to  investigate  the  problems  of  the  origin  and  propa- 
gation of  the  beat  in  the  warm-blooded  heart,  many  experimental  diffi- 
culties of  course  face  us.  In  overcoming  these,  the  first  thing  we  must 
do  is  to  establish  the  structural  relationship  between  cold-blooded  and 
warm-blooded  hearts.     In  the  embryo   of  both  classes  of  animals  the 

132 


Tin;  i'iivsioi,o(JY  (if  tiik   iikakthkat 


183 


heart  arises  as  the  so-called  cardiac  tube.  As  developmenl  proceeds, 
diverticula  grow  ou1  Erom  the  walls  of  this  tube  to  form  the  auricles  and 

ventricles.  In  the  comparatively  simple  heart  of  the  turtle  these  dispo- 
sitions of  the  auricles  and  ventricles  in  relationship  to  the  cardiac  tube 
are  more  or  less  evident  even  in  the  fully  developed  heart,  particularly 
in  the  case  of  the  auricles  (Fig.  49);  but  in  the  heart  of  the  higher 
mammalia  it  is  impossible  by  superficial  examination  alone  to  show  any 
remains  of  the  primitive  cardiac  tube.  More  careful  anatomic  investiga- 
tions during  recent  years  have,  however,  shown  that  it  exists  in  the  form 
of  certain  definite  structures  composed  of  tissue  histologically  quite  dif- 
ferent from  that  of  the  rest  of  the  heart,  and  disposed  in  such  a  manner 


Fig.    49. — Heart  of  tortoise   as   suspended.      B,   body   of   tortoise;    TH ,   threads   to   levers;    CL,   clamp 
holding  aorta;   A,  auricle;    C,   coronary    nerve;    S,   sinus;    V,   ventricle.     (From   Gaskell.) 


as  would  indicate  not  only  that  it  is  derived  from  the  primitive  cardiac 
tube,  but  also  that  it  is  the  main  pathway  along  which  the  beat  is 
transmitted. 

This  primitive  cardiac  tissue  is  much  better  developed  in  certain  re- 
gions than  in  others,  the  first  portion  of  it  to  be  discovered  being  that 
known  as  the  auric  uloventricular  node,  or  the  node  of  Stanley  Kent*  (Figs. 
50  and  51).  This  structure  is  found  at  the  base  of  the  interauricular  sep- 
tum on  the  right  side  and  near  its  posterior  margin.  It  exists  as  a  collection 
of  peculiar  small  primitive  cells  and  fibers,  and  is  continued  downward  as 
a  bundle  of  the  same  peculiar  tissue  to  the  interventricular  septum, 
where,  near  the  union  of  the  posterior  and  median  flaps  of  the  aortic 


'The  discovery  of  this  node  is  often  erroneously  attributed  to  His,  and  called  after  his  name. 


184  THE    CIRCULATION    OP    THE    BLOOD 

valve,  it  bifurcates  so  as  to  send  a  branch  down  each  side  of  the  septum 
immediately  below  the  endocardium.  Each  main  branch,  as  it  proceeds 
downward  on  the  septum,  divides  up  into  an  intricate  system  of  smaller 
branches,  which  become  reflected  over  the  inner  surface  of  the  ventricles, 
where  their  existence  has  been  known  for  some  time  as  the  so-called 


Fig.  50. — Dissection  of  heart  to  show  auriculoventricular  bundle  (Keith);  3,  the  beginning  of 
the  bundle,  known  as  the  A-V  node;  2,  the  bundle  dividing  into  two  branches;  4,  the  branch  run- 
ning  on    the   right   side    of   the   interventricular   septum.      (From    Howell's    Physiology.) 


Fig.  51. — Photograph  of  model  of  the  auriculoventricular  bundle  and  its  ramifications,  con- 
structed from  dissections  of  the  heart  (Miss  De  Witt).  All  of  the  branches  in  the  left  ventricle 
are   not   included.      (From    Howell.) 

Purkinje  fibers.  The  fibers  ultimately  end  in  close  association  with  the 
papillary  muscles.  The  node  and  main  bundle  and  the  two  branches 
before  they  have  begun  to  divide  are  surrounded  by  fibrous  tissue,  and 
they  seem  to  have  a  liberal  blood  supply.  It  is  of  interest  that  they  con- 
tain a  high  percentage  of  glycogen.     In  the  human  heart  the  auriculo- 


THE  PHYSIOLOGY   OF   THE    HEARTBEAT  185 

ventricular  node  and  bundle  measure  aboul  15  mm.  in  Length  and  about 
2  mm.  in  width. 

The  rest  of  the  tissue  between  the  auricles  and  ventricles  is  fibrous 
in  nature,  although  other  connections  like  those  of  the  aurieuloveutricular 
bundle  have  been  described  by  Kent.  One  of  these,  called  the  right  lat- 
eral connection,  runs  between  the  right  auricle  and  the  external  Avail  of 
the  right  ventricle. 

Another,  but  much  smaller,  mass  of  similar  embryonic  cardiac  tissue 
has  more  recently  been  discovered  by  Keith  and  Flack  in  the  parts  of 
the  auricle  which  correspond  anatomically  to  the  sinus  venosus  of  the 
heart  of  cold-blooded  animals — that  is,  in  the  area  lying  between  the 
openings  of  the  vena?  cava?  and  around  the  coronary  sinus.  To  be  more 
explicit,  this  tissue  lies  "in  the  sulcus  terminalis  just  below  the  fork 
formed  by  the  junction  of  the  upper  surface  of  the  auricular  appendix 
with  the  superior  vena  cava."  This  sinoauricular  'node,  as  it  is  called, 
is  more  or  less  club-shaped,  the  blunt  end  of  the  club  being  above,  as 
shown  in  the  accompanying  figure  (Fig.  52).  It  is  important  to  note 
that  there  is  no  direct  connection  visible  between  the  sinoauricular  and 
aurieuloveutricular  nodes  (Fig.  53). 

Another  anatomic  fact  seen  also  in  the  accompanying  figure,  concerns 
the  disposition  of  the  muscular  fibers  of  the  auricle.  These  radiate  in 
bundles  in  a  peculiar  fan-shaped  manner  from  a  point  which  lies  im- 
mediately below  the  sinoauricular  node  to  all  parts  of  the  superficies  of 
the  right  auricle.  This  point  has  been  called  the  concentration  point. 
At  the  termination  of  the  vena?  cava?,  the  muscle  fibers  are  arranged  more 
or  less  circularly. 

Having  become  familiar  with  the  disposition  in  the  mammalian  heart 
of  the  primitive  cardiac  tissue,  along  which  in  the  heart  of  the  lower 
animals  Ave  know  that  the  heartbeat  spreads,  Ave  may  iioav  proceed  to 
examine  the  evidence  shoAving  that  this  tissue  is  also  responsible  for  the 
origination  and  propagation  of  the  beat  in  the  heart  of  mammals.  With 
regard  to  the  origin  of  the  beat  in  a  normally  beating  mammalian  heart, 
it  is  of  course  impossible  to  tell  Avhere  this  takes  place.  If  the  heart  is 
excised,  hoAvever,  it  will  continue  to  beat  for  a  feAv  moments,  and  as  it 
dies  it  will  be  observed  that  the  poAver  of  contraction  remains  in  the  au- 
ricular region,  and  particularly  at  the  bases  of  the  vena?  cava?,  for  a  con- 
siderable time  after  the  ventricles  have  ceased  to  beat.  This  part — the 
ultimum  moriens — is  situated  in  most  hearts  somewhat  loAver  than  the 
sinoauricular  node.  That  it  is  the  last  part  of  the  heart  to  cease  con- 
tracting does  not  necessarily  mean  that  it  is  the  part  of  the  heart  in 
Avhich  the  beat  ordinarily  originates;  it  means  simply  that  this  is  the 
part  of  the  auricle  in  Avhich  the  poAver  of  contraction  remains  for  the 


186 


THE    CIRCULATION    OF    THE   BLOOD 


longest  time  after  death.  Although  the  observation  does  not  enable  us 
to  determine  exactly  where  the  heartbeat  originates,  yet  it  makes  it 
very  probable  that  this  is  somewhere  in  the  auricles;  a  conclusion  which 
is  borne  out  by  many  other  pieces  of  evidence,  such  as  those  obtained  by 


Fig.  52. — Diagram  of  an  auricle  showing  the  arrangement  of  the  muscle  bands;  the  concen- 
tration point  (C.P.);  and  the  outline  of  the  S.A.  node  (S.A.N. ).  The  diagram  is  to  scale,  and 
illustrates  by  the  circles  and  connecting  dotted  lines  the  method  of  leading  off  by  paired  contacts 
and    the    subsequent    orientation.       (From    Thomas    Lewis.) 


i  Auricular  appendage 
--5/noaurfcu/ar  node 


Auriculoventricular  node 
Aurlculoventricular  bundle 


Rights  left  ventricular 
bundles 


Musculi  papillares 


Fig.  53. — Diagram  to  show  the  general  ramifications  of  the  conducting  tissue  in  the  heart  of 
the  mammal.  It  will  be  observed  thai  there  is  none  of  this  tissue  between  the  sinoauriculo-  and 
auriculoventricular    nodes. 


the  study  of  polysphygmograms  (page  273),  of  electrocardiograms  (page 
266),  and  of  observations  on  the  heart  during  heart-block  (page  270). 
Our  problem  therefore  narrows  itself  down  to  determining  the  exact 
point  of  the  right  auricle  at  which  the  beat  originates. 


THE    PHYSIOLOGY   OF   THE    HEARTBEAT  187 

SITE  OF  ORIGIN  OF  THE  BEAT 

The  working  hypothesis  from  which  \vc  may  proceed  to  attack  this 
problem  is  that   the  heat  originates  in  the  sinoauricular  node,  and  to 

put  this  to  the  test,  various  methods  have  been  employed:  (1)  Warming 
or  cooling  or  injuring  the  node  and  noting  the  effect  on  the  heartbeat'. 
Such  procedures  greatly  affect  the  rate  of  the  heartbeat,  whereas  they 
produce  no  change  when  applied  to  other  parts  of  the  heart.  (2)  De- 
termination of  the  comparative  rhythmic  poAver  of  strips  cut  out  from 
different  regions  of  the  auricular  walls.  It  is  greatest  in  those  taken 
from  the  region  of  the  node.  (3)  Determination  by  the  use  of  galvan- 
ometric  curves  of  the  relation  of  the  node  to  the  seat  of  origin  of  cardiac 
impulse.  By  all  these  methods  the  results  indicate  clearly  that  the  beat 
originates  in  the  sinoauricular  node,  but  on  account  of  the  great  im- 
portance in  connection  with  the  interpretation  of  electrocardiograms  in 
man,  it  is  particularly  with  the  result  of  the  third  group  of  experiments 
that  we  will  concern  ourselves  here. 

Evidence  Furnished  by  Studying  the  Current  of  Action  Which 
Accompanies  the  Heartbeat 

To  start  with,  it  is  essential  that  we  make  ourselves  familiar  with 
the  principles  of  the  methods  employed.  These  principles  are  briefly  as 
follows:  When  a  wave  of  contraction  passes  along  a  muscle,  it  is  im- 
mediately preceded  by  a  change  in  electrical  potential,  which  can  be 
detected  by  means  of  a  galvanometer  connected  with  the  muscle  through 
so-called  nonpolarizable  electrodes.  The  galvanometer  employed  must 
be  extremely  sensitive,  and  must  not  vibrate  after  the  current  has  ceased 
to  pass.  The  form  generally  in  use  today  is  known  as  the  string  galva- 
nometer of  Einthoven.  It  differs  from  the  galvanometer  ordinarily  em- 
ployed in  physical  laboratories  in  that  the  current  instead  of  passing 
through  a  coil  of  wire  surrounding  a  magnetic  needle,  passes  through  a 
silverized  quartz  thread  suspended  in  the  strong  magnetic  field  which 
exists  between  the  two  opposing  jioles  of  a  horseshoe  electromagnet. 
The  string  is  thus  surrounded  on  all  sides  by  innumerable  lines  of  force 
extending  between  the  two  poles  of  the  magnet.  When  a  current,  how- 
ever small,  passes  along  the  string,  it  will  generate  lines  of  force  of  its 
own,  and  these  by  reacting  with  the  stationary  lines  of  force  of  the  field 
will  cause  the  string  to  move.  The  string  is  placed  in  the  pathway  of  a 
strong  beam  of  light,  and  its  shadow,  after  being  magnified  by  lenses, 
is  projected  on  a  moving  photographic  plate  or  paper  arranged  in  a 
suitable  holder.  The  nonpolarizable  electrodes  referred  to  are  employed 
in  place  of  ordinary  electrodes  in  order  to  obviate  the  generation  of  elec- 


188  THE    CIRCULATION    OF    THE    BLOOD 

trie  currents  set  up  by  the  contact  of  metal  with  the  saline  constituents 
of  the  muscle  juices. 

If  we  connect  a  galvanometer  by  means  of  nonpolarizable  electrodes 
with  two  parts  of  a  denervated  muscle  (the  curarized  sartorius  of  the 
frog),  it  will  be  found  that  a  current  is  set  up  whenever  a  wave  of  con- 
traction passes  over  the  muscle  from  one  end  to  the  other.  The  part 
which  first  contracts  becomes  electrically  negative  to  the  rest  of  the  muscle, 
but  as  the  wave  of  contraction  passes  along  it,  the  "negativity"  de- 
creases at  the  end  at  which  the  wave  started  until,  when  the  wave  has 
reached  the  middle  of  the  strip,  neither  end  of  the  muscle  shows  any 
difference  in  potential,  so  that  the  string  comes  back  to  a  position  of 
rest.  However,  as  the  contraction  wave  reaches  the  farther  end  of  the 
muscle,  this  lead  in  turn  becomes  negative,  and  the  string  swings  in  the 


liiiiiiiiiiiiiiiiiiiiiiiinl 


Fig.  54. — Diagram  to  illustrate  the  development  and  spread  of  the  wave  of  negativity  in  a 
strip  of  muscle  (curarized  sartorius)  when  stimulated  at  the  end  (P).  The  shaded  portions  show 
the  position  of  the  negativitv.  The  portion  of  the  curve  drawn  by  the  deflections  of  the  galvanom- 
eter   at    each    stage    are    shown    at    the    right    (a,    b,    c,    and    d).      (After    Lewis.) 

opposite  direction  (Fig.  54).  From  this  comparatively  simple  experiment 
it  can  be  seen  that  a  muscular  contraction  wave  arises  at  the  electrode  which 
is  negative  first,  and  that  the  movement  of  the  string  of  the  galvanometer  is 
most  marked — that  is,  the  deflection  is  greatest — when  the  two  electrodes 
are  applied  at  the  extreme  ends  of  the  muscle.  "When  they  are  brought 
closer  together,  the  initial  deflection  becomes  much  less  marked;  in  other 
words,  the  amplitude  of  the  negative  wave  is  greatest  when  the  time 
interval  between  the  receipt  of  the  excitation  at  the  two  contacts  is 
greatest. 

The  application  of  these  facts  to  the  study  of  the,  initiation  of  the  beat 
in  the  auricle  requires  that  we  should  consider  another  proposition: 
namely,  if  a  pair  of  contacts  are  arranged  in  the  center  of  a  circular 
sheet  of  muscle  and  the  edge  of  this  sheet  is  stimulated  at  different 


THE    PHYSIOLOGY   OF   THE    HEARTBEAT  189 

points,  the  amplitude  of  deflection  of  ;i  galvanometer  connected  with  the 
pair  of  contacts  will  ho  most  pronounced  when  these  are  radial  to  the 
points  of  stimulation,  for  under  these  conditions  it  is  evident  that  the 
greatesl  possible  difference  will  exist  between  the  intervals  required  for 
the  wave  1<>  reach  each  contact. 

Bearing  these  principles  in  mind,  we  may  now  proceed  to  examine  the 
evidence  pointing  to  the  origin  of  the  heartbeat  at  the  sinoauricular  node: 
(1)  When  two  electrodes  are  applied  at  different  points  of  the  au- 
ricle, the  amplitude  of  movement  of  the  string  of  the  galvanometer 
produced  by  each  heartbeat  is  greatesl  when  the  line  joining  the  elec- 
trodes converges  on  the  sinoauricular  node.  To  make  this  clear  the 
movement  of  the  string  must  ho  photographed  in  the  manner  above 
described,  the  resulting  tracing  being  called  an  electrocardiogram.  From 
the  experiments  with  the  circular  sheet  of  muscle  alluded  to  it  is  evident 
that  the  stimulus  to  produce  this  result  must  have  arisen  in  the  neigh- 
borhood of  the  node.  (2)  Tf  one  electrode  is  placed  on  the  sinoauricular 
node  and  the  other  electrode  is  moved  about  from  place  to  place  on  the 
auricle,  the  deflection  being  noted  at  each  new  position,  the  electrode 
on  the  node  will  always  he  found  to  he  negative  to  the  other  electrode;* 
which,  however,  will  not  he  the  case. if  both  electrodes  are  moved  about 
on  other  parts  of  the  auricle. 

(3)  As  Ave  shall  see  immediately,  the  current  of  action  of  the  beating 
heart  may  he  recorded  by  connecting  a  galvanometer  with  various  parts 
of  the  body;  for  example  with  the  right  fore  limb  and  the  left  hind 
limb.  On  the  electrocardiogram  thus  obtained  are  several  waves,  one 
of  which,  called  the  P-wave,  can  easily  he  shown  to  correspond  to  the 
contraction  of  the  auricle  (see  Fig.  261).  If  now  we  compare  such  elec- 
trocardiograms Avith  those  obtained  Avhile  contractions  of  the  auricle 
are  produced  by  applying  artificial  stimulation  to  various  parts  of  it, 
it  Avill  be  found  that  the  artificial  simulates  the  normal  curve  only  when 
the  stimulated  part  is  in  the  neighborhood  of  the  sinoauricular  node. 
In  other  words,  it  is  only  when  the  stimulus  is  applied  to  the  sinoauric- 
ular node  that  a  characteristic  P-wave  is  obtained.  "When  the  appendix 
or  the  superior  Arena  cava  is  stimulated,  the  P-wave  is  distorted  although 
the  other  waves  of  the  electrocardiogram  may  be  normal. 

(4)  By  taking  simultaneous  electrocardiograms  from  direct  leads 
placed  on  the  auricle  and  comparing  the  record  Avith  that  of  a  standard 
limb  lead  taken  simultaneously,  Ave  shall  find  by  exact  measurement  that 
the  time  of  onset  of  the  excitation  Avave  of  the  auricle,  as  measured  in 
relationship  to  the  P-wave  on  the  standard  electrocardiogram,  is  shortest 

*The  connections  between  the  electrodes  and  galvanometer  are  always  arranged  so  that  any 
upward  movement  of  the  shadow  of  the  string  above  the  line  of  equal  potential  at  the  two  electrodes 
indicates  electric  negativity. 


190 


THE    CIRCULATION    OP    THE    I5LOOD 


when  one  electrode  is  over  the  upper  end  of  the  sinoauricular  node,  and 
that  in  other  regions  of  the  auricle  it  always  appears  at  a  later  interval. 
Further  details  on  this  subject  will  be  found  in  the  papers  by  Eyster  and 
Meeks  and  in  Lewis,  monographs. 

Frequently,  in  taking  electrocardiograms  from  different  parts  of  the  auricle,  it  is 
found  that  certain  of  the  curves  show  small  waves  of  positivity  below  the  line  of  equal 
potential  preceding  the  main  wave  of  negativity.  These  initial  deflections  are  most 
marked  when  both  the  electrodes  are  far  removed  from  the  sinoauricular  node— for  ex- 
ample, when  they  are  placed  on  the  auricular  appendix;  but  they  are  never  present  when 


Fig.  55. — Simultaneous  electrocardiograms  to  show  the  cause  for  extrinsic  deflections.  The 
upper  curves  are  from  the  appendix  and  the  lower  ones  from  lead  II.  The  chief  or  intrinsic 
deflection  (Tre)  is  seen  to  disappear  in  the  right-hand  appendix  electrocardiogram,  because  the 
base  of  the  appendix  has  been  crushed.  The  extrinsic  deflection  (Ex)  remains,  as  do  the  ven- 
tricular  deflections    (I'1    ]'-).      (From    Lewis.) 

one  of  the  electrodes  is  placed  on  the  sinoauricular  node  itself.  In  other  words,  curves 
taken  from  leads  at  a  distance  from  the  sinoauricular  node  are  mure  or  less  composite 
in  form,  being  made  up  partly  of  the  main  deflection  due  to  the  arrival  of  the  excitation 
and  partly  of  the  secondary  deflections  dependent  upon  extrinsic  influences  acting  on 
the  electrodes;  that  is,  the  electrode  picks  up  electric  discharges  from  distant  areas  of 
muscle  while  these  are  in  a.  condition  of  contraction  (Fig.  55).  From  these  considera- 
tions it  follows  that  the  intervals  between  the  intrinsic  and  extrinsic  deflections 
should  be  longest  in  leads  that  are  farthest  from  the  node,  and  gradually  become 
less  as  one  of  the  contacts  approaches  -the  node,  until  over  this  structure  the  ex- 
trinsic deflection  is  no  longer  recorded.     Such  has  been  found  to  be  the  case. 


CHAPTER  XXII 

THE  PHYSIOLOGY  OF  THE  HEARTBEAT  (Cont'd) 

THE  ORIGIN  AND  PROPAGATION  OF  THE  BEAT  (Cont'd)— 

FIBRILLATION 

Mode  of  Propagation  in  the  Auricles 

From  the  mass  of  evidence  Ave  have  little  doubt  that  the  heartbeat 
originates  in  the  sinoauricular  node,  and  the  question  now  presents  itself 
as  to  how  the  beat  is  propagated  over  the  remainder  of  the  auricles  and 
into  the  ventricles.  Regarding  the  propagation  of  the  beat  over  the 
auricles,  two  possibilities  exist:  (1)  it  may  spread  uniformly  over  the 
muscular  tissue  of  the  auricular  wall  until  it  reaches  the  auriculoventric- 
ular  node,  or  (2)  there  may  be  laid  down  between  the  sinoauricular  and 
the  auriculoventricular  node  a  special  strand  of  highly  conducting  tissue. 
It  is  no  argument  against  this  second  possibility  that  Ave  should  so  far 
have  been  unable  by  histologic  methods  to  differentiate  any  such  struc- 
tures. 

There  is  considerable  practical  importance  attached  to  the  solution  of 
these  questions,  particularly  with  regard  to  the  cause  of  certain  types 
of  cardiac  arrhythmia,  such,  for  example,  as  that  knoAvn  as  nodal  rhythm. 
Thus,  it  is  evident  that  if  the  beat  is  transmitted  uniformly  over  the 
muscular  tissue  of  the  auricle,  then  the  Avhole  auricle  will  have  con- 
tracted before  the  beat  has  reached  the  auriculoventricular  bundle,  by 
Avhich  it  is  then  transmitted  to  the  ventricles.  On  the  other  hand,  if  the 
beat  should  travel  betAveen  the  tAvo  nodes  by  special  conducting  tissue, 
then  the  impulse  will  have  arrived  at  the  auriculoventricular  node  be- 
fore the  auricle  has  contracted.  As  a  matter  of  fact,  it  is  not  quite  settled 
yet  as  to  which  of  these  two  views  is  the  correct  one,  although  the  balance 
of  evidence  seems  to  favor  the  former — that  is,  that  the  wave  is  transmitted 
uniformly  over  the  muscular  tissue  of  the  auricle.     (LeAvis.) 

The  methods  employed  in  attacking  the  problem  have  been  essentially 
the  same  as  those  described  above.  One  of  them  may  be  called  the  direct, 
the  other  the  indirect.  In  the  former,  a  series  of  pairs  of  contacts  is 
placed  on  the  auricle,  each  pair  being  in  a  radial  direction  to  the  sino- 
auricular node.  The  time  at  Avhich  the  excitatory  process  arrives  at  that 
contact  of  each  pair  Avhich  is  proximal  to  the  sinoauricular  node  is  accu- 

191 


1!)2  THE  CIRCULATION   OF  THE  BLOOD 

rately  determined  from  the  galvanometric  record.  Tlio  exact  distance  be- 
tween the  contact  and  the  sinoauricular  node  is  then  measured  and  from 
the  data  the  average  transmission  time  is  estimated.  From  his  results 
Lewis3  concludes  that  the  transmission  rates  are  uniform  from  the  node 
to  all  parts  of  the  auricle,  with  the  exception  of  the  superior  vena  cava. 
in  which  the  rate  is  considerably  lower.  One  thousand  millimeters  per 
second  represents  very  fairly  the  average  rate  at  -which  ihe  excitation 
wave  travels.  On  the  other  hand,  Eyster  and  Meek8  state  that  the  wave 
is  propagated  throughout  the  sinus  node,  and  that  it  spreads  to  the 
contiguous  vena?  cava?  and  to  the  auriculoventrieular  node  with  con- 
siderable rapidity,  reaching  the  mouth  of  the  superior  vena  cava  in  0.01 
second,  whereas  its  passage  to  the  auricle  itself  takes  0.02  second.  There  is 
therefore  a  delay  in  the  passage  of  the  wave  to  the  auricle,  which  indi- 
cates that  the  excitation  must  spread  to  the  auriculoventrieular  node  be- 
fore involving  the  right  atrium.  These  authors  conclude  that  "this  leads 
to  the  inevitable  conclusion  that  the  cardiac  impulse  spreads  to  the  ven- 
tricle and  to  the  right  auricle  by  different  paths,  and  does  not  pass  to 
the  ventricle  through  the  auricle,  as  ordinarily  stated." 

In  the  second,  or  indirect,  method,  the  onset  of  the  negative  wave  from 
different  leads  in  the  auricle  is  compared  against  a  standard.  For  the 
standard  Eyster  and  Meek  have  used  the  record  of  the  mechanical  sys- 
tole of  the  auricle,  but  the  interpretation  of  the  result  is  extremely  dif- 
ficult on  account  of  the  rate  at  which  the  changes  are  occurring.  Lewis, 
on  the  other  hand,  has  used  the  standard  electrocardiogram  for  purposes 
of  comparison. 

Mode  of  Propagation  of  the  Beat  to  the  Ventricles 

After  reaching  the  auriculoventrieular  node,  the  beat  is  transmitted  to 
the  ventricles  along  the  auriculoventrieular  bundle — a  fact  which  has  been 
most  clearly  demonstrated  by  the  experiments  on  heart-block.  We  have  al- 
ready seen  (page  174)  that  although  each  chamber  of  the  heart  of  a 
turtle  or  frog  has  a  rhythm  of  its  own,  this  is  much  more  pronounced  at 
the  venous  end  of  the  heart,  and  when  the  transmission  of  the  beat  to  the 
ventricles  from  the  auricles  is  obstructed  or  blocked,  as  by  compression 
or  jDartial  cutting  at  the  auriculoventrieular  junction,  the  ventricles, 
after  coming  to  a  standstill  for  a  time,  subsequently  contract  with  a 
rhythm  which  is  entirely  independent  of  that  of  the  auricles. 

In  the  mammalian  heart  the  same  results  may  be  obtained  by  arrang- 
ing a  clamp  so  that  it  compresses  practically  nothing  but  the  auriculo- 
ventrieular bundle  (Erlanger.)  If  the  compression  is  extreme,  the 
rhythm  of  the  ventricles  is  quite  independent  of  that  of  the  auricles,  but 
if  it  is  only  partial,  the  ventricular  systoles  follow  regularly  every  see- 


TIIE   PHYSIOLOGY   OF   THE    HEARTBEAT  1  B3 

ond,  third,  or  fourth  auricular  contraction.  It'  after  such  a  complete  or 
partial  heart-block  has  been  instituted,  the  clamp  is  removed,  it  will 
usually  be  found  that  the  heart-block  disappears  and  the  auricular  and 
ventricular  contractions  fall  back  into  their  usual  sequence.  The  im- 
portance of  this  discovery,  apart  from  its  physiologic  interest,  rests  in 
the  fact  that  it  is  exactly  duplicated  in  clinical  experience.  If  the  pulse 
tracing  of  the  radial  artery  is  compared  with  that  of  the  jugular  vein 
in  certain  types  of  heart  disease,  it  -will  be  found  that  the  auricle  is  beat- 
ing tAvo  or  three  times  more  quickly  than  the  ventricles.  In  many  of 
these  cases  it  has  been  found  on  autopsy  that  definite  lesions  often  syphi- 
litic in  nature  involve  the  auriculoventricular  bundle.  In  other  cases. 
however,  such  lesions  have  not  been  discovered.  Sometimes  the  bundle 
is  so  severely  diseased  that  the  block  is  complete,  the  ventricles  con- 
tracting quite  independently  of  the  auricle  (Stokes-Adams  syndrome.) 
In  such  cases  it  is  assumed  that  the  beat  originates  in  the  uninjured  part 
of  the  bundle  below  the  seat  of  the  block.  It  should  be  pointed  out  here, 
however,  that  all  cases  of  slow  pulse  in  the  arteries  are  not  necessarily 
dependent  upon  heart-block,  but  may  depend  upon  a  slow  beat  of  the 
auricle  itself.     This  is  called  bradycardia. 

Sometimes  after  complete  destruction  of  the  auriculoventricular  bun- 
dle the  beat  continues  to  be  transmitted  to  the  ventricle,  and  conversely 
this  transmission  has  sometimes  been  observed  to  be  upset  by  lesions  not 
affecting  the  bundle.  The  explanation  of  both  of  these  exceptional  re- 
sults almost  certainly  is  that  the  right  lateral  connection  described  above 
(page  184)  is  serving  as  the  main  pathway  of  transmission  for  the  beat. 

The  facility  of  conduction  through  the  auriculoventricular  bundle  is 
subject  to  alteration  by  the  impulses  passing  to  it  along  the  vagus  nerve, 
particularly  the  left  vagus.  It  can  also  be  altered  by  certain  drugs, 
especially  digitalis  and  strophanthin.  The  clear  demonstration  that  it  is 
along  this  bundle  that  the  beat  is  transmitted  is  strong  evidence  in  favor 
of  the  myogenic  hypothesis  (page  171)  concerning  the  transmission  of 
the  heartbeat,  but  it  does  not  necessarily  disprove  the  neurogenic  hypoth- 
esis, for  histologic  investigation  has  shown  that  the  bundle  is  closely 
surrounded  by  an  intimate  plexus  of  nerve  fibers. 

Spread  of  the  Beat  in  the  Ventricle 

After  the  impulse  has  been  transmitted  by  the  bundle  into  the  ven- 
tricles, it  spreads  along  the  many  branches  into  which,  as  we  have  seen, 
the  two  main  divisions  of  this  bundle  separate.  The  first  part  of  the 
ventricular  musculature  to  contract  is  therefore  located  near  the  ter- 
mination of  these  branches,  at  the  papillary  muscles.  That  these  should 
contract  before  the  rest  of  the  muscle  of  the  ventricles,  has  an  obvious 


194 


THE    CIRCULATION    OP    TIIK    MLOOD 


significance  in  connection  with  their  function  of  tightening  the  chordae 
tendineae  so  as  to  prevent  any  bulging  of  the  flaps  of  the  auriculoven- 
tricular  valve  into  the  auricles  when,  at  the  beginning  of  the  prcsphygmic 
period,  the  high  intraventricular  pressure  is  brought  to  bear  on  their 
under  surfaces.  After  starting  at  this  point  in  the  ventricle,  the  con- 
traction wave  seems  to  spread  farther  through  the  ventricular  muscle  at 
a  fairly  uniform  rate. 

Investigation  of  this  problem  by  means  of  the  galvanometer  has  been 
technically  a  very  difficult  matter,  and  the  details  of  the  researches  by 
Lewis  and  his  pupils  have  not  as  yet  been  published  in  full.  According 
to  the  preliminary  communications  at  hand,  however,3*  it  appears  that, 


•0*6/ 


Fig.  56. — Diagram  of  experiment  by  Lewis  showing  the  times  at  which  the  excitation  wave 
appeared  on  the  front  of  the  heart  relative  to  the  upstroke  of  R  in  lead  II.  R.A.,  right  appen- 
dix;   D.B.L.,   descending   branch    of   left   coronary   artery.      (From    Thomas    Lewis.) 


when  noupolarizable  electrodes  are  placed  at  various  parts  of  the  outer 
aspect  of  the  ventricle,  and  comparison  made  of  the  moments  at  which 
the  cardiac  impulse  arrives,  as  judged  by  the  appearance  of  the  excita- 
tion wave  relative  to  R  in  a  standard  electrocardiogram,  it  has  been 
found  that  the  time  of  arrival  bears  no  relationship  to  the  anatomic  ar- 
rangement of  the  muscle  bundles  of  the  ventricle.  It  arrives  early  and 
simultaneously  over  an  area  of  the  surface  near  the  anterior  attachment 
of  the  wall  of  the  right  ventricle.  It  arrives  late  at  the  base  of  the  right 
ventricle  and  in  the  part  near  the  posterior  intraventricular  groove. 
Histologic  examination  has  shown  that  the  branches  of  the  right  division 
of  the  auriculoventricular  bundle  are  most  closely  connected  with  the 


Tin:   PHTSTOLOGY.    OF   THE    HEARTBEAT  195 

place  where  the  wave  arrives  earliest.  Somewhal  different  results  are 
obtained  from  the  lefl  ventricle,  bu1  again  they  are  dependent  upon  the 
relationship  of  the  pari  to  the  Purkinje  fibers  l  Fig.  56). 

FIBRILLATION  OF  THE  HEART 

Ventricles 

The  even  spread  of  the  wave  of  contraction  over  the  heart  depends  on 
tlic  uniform  excitability  of  the  muscular  fibers.  If  certain  of  the  muscu- 
lar fibers,  or  bundles  of  fibers,  have  a  greater  or  less  excitability  than 
others,  then,  when  the  stimulus  to  contract  arrives,  it  will  not  produce 
a  uniform  contraction  of  neighboring  bundles,  and  coordinated  action  of 
the  cardiac  musculature  will  give  place  to  a  confused  movement  in  which 
each  part  of  the  heart  is  contracting  independently  of  the  rest.  This 
fibrillation,  or  delirium  cordis,  as  it  is  called,  can  be  produced  by  a  lar^e 
variety  of  experimental  methods,  such,  for  example,  as  by  stimulating 
the  ventricles  with  induced  electric  shocks,  or  by  ligation  of  a  large 
branch  of  the  coronary  artery,  or  by  the  injection  of  lycopodium  spores 
into  the  coronary  circulation,  or  by  mechanical  stimulation  of  the  heart 
in  the  region  of  the  auriculoventricular  bundle. 

Fibrillation  of  the  ventricles  is  undoubtedly  a  common  cause  of  death 
in  man,  for  of  course  the  confused  movements  make  the  ventricles  in- 
capable of  contracting  on  the  contents  of  the  heart.  It  is  a  condition 
which  can  probably  never  be  recovered  from  in  the  higher  animals,  but 
it  is  of  interest  that  the  ease  with  which  it  is  set  up  as  the  result  of  the 
application  of  an  electric  stimulus  varies  to  a  marked  degree  in  differ- 
ent animals,  and  that  in  those  hearts  in  which  fibrillation  can  be  elic- 
ited only  with  difficulty,  recovery  can  usually  be  effected  either  by  stop- 
ping the  heart  by  means  of  cold  and  then  allowing  it  to  beat  again,  or 
by  the  administration  of  epinephrine.  Of  the  hearts  investigated  in 
this  way,  that  of  the  rat  has  been  found  to  be  most  resistant  to  stimula- 
tion; then  in  order  come  those  of  the  rabbit,  the  cat,  the  dog,  and  the 
horse.  There  is  good  reason  to  believe  that  the  heart  of  man  is  readily 
affected.  Fibrillation  of  the  ventricle  is  undoubtedly  the  main  cause  of 
death  in  most  cases  of  electrocution.  Curiously  enough,  however,  it  has 
been  stated  that,  whereas,  a  current  of  ordinary  intensity  (2300  volts 
alternating  current)  produces  ventricular  fibrillation  in  the  heart  of  cer- 
tain of  the  lower  animals,  at  least  in  that  of  the  horse,  a  very  much 
stronger  current  does  not  do  so,  and  may  indeed  cause  ventricular  fibril- 
lation produced  by  a  more  moderate  voltage  to  disappear.  Unfortu- 
nately, however,  these  stronger  currents  produce  irreparable  damage  in 


196  THE    CIRCULATION    OF    THE    BLOOD 

the  central  nervous  system,  so  that  the  method  of  applying  stronger  cur- 
rents, even  were  it  feasible  to  do  so  quickly  enough,  would  be  of  no 
therapeutic  value  in  removing  fibrillation. 

The  disappointing  results  that  have  followed  the  repeated  attempts 
to  resuscitate  persons  hilled  accidentally  by  electric  shocks  is  undoubt- 
edly dependent  upon  the  fact  that  in  the  heart  of  man  it  is  impossible 
to  bring  back  the  normal  beat  after  the  ventricles  have  been  thrown  into 
fibrillation.  Fibrillation  of  the  ventricle  is  also  the  cause  of  the  sudden 
cardiac  failure  occurring  when  blood  clots  or  emboli  cause  a  blockage 
of  the  coronary  circulation  (it  is  sometimes  the  cause  of  angina  pec- 
toris, for  example).  It  must  also  be  remembered  in  clinical  practice 
that  mechanical  stimulation  of  the  ventricles  may  produce  fibrillation,  so 
that  in  attempted  resuscitation  by  cardiac  massage  care  should  be  taken 
not  to  apply  this  too  vigorously. 

Auricles 

Although  ventricular  fibrillation  is  seldom  recovered  from,  it  has  been 
clearly  shown  in  recent  years  that  fibrillation  of  the  auricles  is  relatively 
common  and  that  it  is  by  no  means  immediately  fatal.  Indeed  it  is  one 
of  the  most  common  of  the  chronic  cardiac  disorders  in  man.  Auricular 
fibrillation  can  be  produced  experimentally  by  the  application  of  a 
strong  electric  stimulus  to  the  auricles.  If,  however,  a  weaker  stimulus 
is  applied,  the  auricles  do  not  go  into  typical  fibrillation,  but  come  to 
beat  at  a  very  rapid  and  regular  rate,  perhaps  three  or  four  hundred  a 
minute.  This  condition  is  called  ''auricular  flutter."  and  is  quite  fre- 
quently observed  in  the  clinic. 

The  influence  of  auricular  fibrillation  and  flutter  on  the  beat  of  the  ven- 
tricle is  an  extremely  important  one  in  connection  with  the  irregular- 
ities of  the  heart  observed  in  man,  and  this  influence  in  most  eases  is 
explained  by  considering  (1)  the  narrowness  of  the  path  (in  the  auric- 
uloventricular  bundle)  along  which  the  impulses  have  to  travel,  and  (2) 
the  varying  conditions  of  excitability  of  the  ventricular  muscle,  depend- 
ing upon  the  existence  of  the  refractory  phase  (page  180). 

In  auricular  flutter,  when  three  or  four  hundred  impulses  per  minute 
are  passing  along  the  bundle  to  the  ventricle,  the  contraction  produced 
by  the  first  one  will  scarcely  have  started  before  the  second  and  imme- 
diately succeeding  ones  arrive,  so  that  the  ventricle  will  beat  at  a  rate 
that  is  much  less  than  that  of  the  auricle,  and  a  condition  simulating 
heart-block  will  become  established.  The  characteristic  feature  which 
distinguishes  this  from  true  heart-block,  however,  is  the  fact  that  the 
ventricular  rate  is  above  normal,  whereas  in  true  heart-block  the  rate 
is   much   below   normal.      By    means    of   the    electrocardiogram    or   by 


THE    PHYSIOLoiiV    OK    Till:    HEARTBEAT  197 

polysphygmographic  tracings,  it   can  also  be  Bhown  that  the  auricle  is 
beating  with  perfect  regularity  although  very  rapidly. 

In  auricular  fibrillation  the  ventricles  obviously  will  respond  a1  a  very 
irregular  rate  to  the  impulses  transmitted  to  them.,  and  the  auricular 
contractions,  if  examined  by  the  methods  above  described,  will  show  no 
regular  sequence.  Further  details  oi*  the  method  of  eliciting  these  signs 
will  be  described  later  (page  2G6). 


CHAPTER  XXIII 
THE  BLOODFLOW  IN  THE  ARTERIES 

THE  PULSES 

Returning  to  the  physical  laws  that  govern  the  circulation  of  the  blood, 
we  may  now  consider  the  temporary  changes  produced  in  the  bloodflow 
in  the  arteries  by  each  systolic  discharge.  These  changes  go  under  the 
general  term  of  the  pulses,  of  which  three  may  be  distinguished:  (1) 
the  pressure  pulse,  or  the  pulsatile  increase  of  pressure  produced  by 
each  heartbeat  (see  page  127)  ;  (2)  the  velocity  pulse,  or  pulsatile  accel- 
eration of  velocity;  and  (3)  the  palpable  pulse,  or  the  pulsatile  expansion 
of  the  walls  of  the  blood  vessels  produced  by  the  sudden  change  of  blood 
pressure  in  their  interior.  The  general  characteristics  of  the  three 
pulses  are  the  same,  certain  features  being  however  more  pronounced 
in  one  than  in  another. 

General  Characteristics 

Rate  of  Transmission  of  Pulse  Wave. — The  rate  of  transmission  of 
the  pulse  wave  can  be  determined  by  taking  simultaneous  tracings  of 
the  pulses  from  two  far  distant  parts  of  the  arterial  system  along  with 
accurate  time-tracings.  From  records  (cf.  Fig.  98)  taken  from  the  apex  or 
the  carotid  and  radial  arteries  we  can  determine  how  long  it  takes  for 
the  beginning  of  the  pulse  wave  to  travel  to  the  radial  artery  from  the 
point  in  the  aorta  from  which  the  carotid  artery  springs.  We  shall  find 
that  it  takes  about  one-tenth  of  a  second,  which,  considering  the  length 
of  the  artery  involved,  would  work  out  as  a  transmission  velocity  of 
about  seven  meters  per  second  or  about  seventeen  miles  an  hour.  The 
pulse  therefore  travels  along  the  blood  vessels  at  a  much  greater  speed 
than  the  blood  itself  is  moving,  this  being,  as  we  shall  see  immediately, 
about  0.5  meters  per  second  in  the  larger  blood  vessels. 

The  pulse  is  a  wave  of  sudden  increase  in  pressure  and  velocity  pass- 
ing along  a  stream  which  is  flowing  in  the  same  direction  with  a  cer- 
tain more  permanent  pressure  and  velocity.  A  simple  physical  experi- 
ment may  serve  to  make  this  clear:  If  the  first  of  a  row  of  billiard  balls 
be  tapped  with  the  cue,  the  end  balls  will  fly  off  while  the  others  are 
moving  sloAvly  along  in  the  direction  of  the  stroke.  Each  ball  becomes 
accelerated  by  the  ball  behind  it,  and  imparts  its  influence  to  the  ball 

198 


THE    BLOODFLCW    IN    THE   ARTERIES  199 

in  front.  In  other  words,  a  pulsatile  acceleration  of  velocity  is  produced 
by  a  pulsatile  change  in  pressure  between  each  two  balls.  The  existence 
of  a  pulse  wave  going  in  the  same  direction  bu1  quicker  than  a  moving 
column  of  fluid  can  also  he  illustrated  by  observing  the  waves  traveling 
down  a  stream  when  a  stone  is  thrown  into  it. 

The  length  of  the  pulse  wave  is  such  that  the  beginning  of  it  has  ar- 
rived at  the  periphery  of  the  arterial  system  before  the  end  has  disap- 
peared from  the  beginning  of  the  aorta.  This  is  important  to  remem- 
ber, for  it  is  a  common  mistake  to  think  of  the  wave  as  being  a  local 
one.  The  determination  of  the  length  of  the  pulse  wave  depends  upon 
the  following  equation:  L  =  VT,  where  L  equals  the  length  of  the  pulse 
wave,  V  its  velocity  of  transmission,  and  T  its  duration  at  a  given  point 
in  the  artery.  Under  ordinary  circumstances  L  would  usually  work  out 
from  3.25  to  4.5  meters. 

The  rate  of  transmission  of  the  pulse  wave  varies  according  to  the 
rigidity  of  the  walls  of  the  arteries.  To  understand  why  this  should  be 
so,  it  will  be  well  for  a  moment  to  consider  the  physical  conditions 
upon  which  the  pulse  wave  depends.  If  we  connect  a  piece  of  rigid 
tube  with  the  nozzle  of  a  large  syringe,  with  each  movement  of  the  pis- 
ton a  wave  of  pressure  will  be  transmitted  to  the  fluid  in  the  tube,  along 
which  it  will  travel  at  such  a  high  velocity  that  it  will  arrive  at  the 
free  end  of  the  tube  almost  instantaneously,  and  incidentally  the  out- 
flow of  fluid  from  the  end  of  the  tube  with  each  compression  of  the 
pump  Mill  be  exactly  equal  to  that  represented  by  the  movement  of  the 
piston.  If,  on  the  other  hand,  an  elastic  tube  is  employed,  it  will  be 
found  that  the  sudden  increase  of  pressure  produced  by  each  stroke  of 
the  pump  causes  a  distention  of- the  walls,  which  travels  along  the  tube 
as  a  wrave  at  a  readily  measurable  velocity,  which  is  slower  the  more 
extensible  the  tube.  Moreover,  the  outflow  of  fluid  from  the  free  end 
of  the  tube  will  continue  for  some  time  after  the  cessation  of  the  move- 
ment of  the  pump.  What  happens  in  the  tube  with  each  discharge  of 
the  fluid  is  that  the  portion  which  is  immediately  adjacent  to  the  pump 
undergoes  distention  and,  being  elastic,  tends  immediately  afterward  to 
recoil  and  thus  exert  a  recoil  pressure  on  the  fluid  contained  in  the  tube. 
As  a  result,  pressure  weaves  are  set  up  in  the  fluid  in  all  directions.  Those 
that  travel  back  come  to  a  stop  because  of  the  piston,  wrhile  those  that 
travel  distally  act  on  the  fluid  in  front  of  them  so  as  to  accelerate  it 
and  by  temporarily  raising  its  pressure  distend  the  next  segment  of  the 
vessel  wall,  until  the  end  of  the  tube  is  reached.  From  this  considera- 
tion it  is  clear  that  the  more  extensible  and  elastic  the  wall  of  the  tube 
is,  the  longer  will  it  take  for  the  wave  of  pressure  to  travel  from  one 
end  to  the  other. 


200 


THE    CIRCULATION    OF    THE   BLOOD 


Alteration  in  the  rate  of  transmission  of  the  pulse  wave  in  the  arter- 
ies of  man  depends  entirely  upon  an  application  of  these  principles. 
When  the  arteries  become  hardened  in  old  age,  the  rate  of  transmission 
of  the  pulse  wave  is  markedly  increased.  The  pulse  is  also  transmitted 
more  rapidly  in  the  vessels  of  the  lower  extremities  than  in  those  of  the 
upper,  since  in  the  former  the  blood  vessels  are  somewhat  more  rigid. 
Delay  in  the  transmission  of  the  pulse  wave  is  further  observed  as  one 
of  the  signs  of  aneurism  in  a  vessel ;  as  is  well  known,  aneurism  of  the 
subclavian  artery  on  one  side  causes  a  delay  of  the  pulse  on  that  side 
that  is  perceptible  to  the  fingers. 

The  Contour  of  the  Pulse  Curves 

For  more  particular  study  of  the  exact  contour  of  the  pulse  wave,  and 
especially  for  determining  the  time  relationships  of  the  secondary  waves, 


Fig.  57. — Diagram  of  Chauveau's  dromograph.  a,  tube  for  introduction  into  the  lumen  of  the 
artery,  and  containing  a  needle  or  vane,  which  passes  through  the  elastic  membrane  in  its  side 
and  moves  by  the  impulse  of  the  blood  current;  c,  graduated  scale  for  measuring  the  ex.tent  of 
the  oscillations  of  the  needle. 


a  large  variety  of  methods  of  varying  degrees  of  accuracy  have  been 
elaborated  for  each  kind  of  pulse. 

Those  devised  for  measuring  the  pressure  pulse  have  already  been  de- 
scribed (see  page  127),  and  for  the  other  pulses  they  are  as  follows: 

Velocity  Pulse. — Much  ingenuity  has  been  displayed  in  the  elabora- 
tion-of  methods  for  recording  the  velocity  pulse.  In  one  of  these  the 
artery  is  cut  across  and  the  ends  attached  to  a  tube,  into  the  lumen 
of  which  projects  a  paddle  or  vane  articulated  with  a  light  lever,  which 
passes  through  its  wall,  (see  Fig.  57).  The  vane  floats  in  the  blood 
stream,  and  the  outer  end  of  the  lever  to  which  it  is  attached  is  con- 
nected with  some  device  to  record  its  movements,  which  vary  with  the 
velocity  of  bloodflow  (hemodromograph).  Another  method  consists  in 
the  application  of  the  instrument  known  as  Pitot's  tube  used  by  phys- 
icists.    This  consists  of  a  horizontal  tube  having  two  side  tubes,  each  of 


THE    i:l.(MH»ll.«»\V     IN    Till;    ARTKKIKS 


201 


which  is  connected  at  its  outer  end  with  n  manometer  and  prolonged 
inside  the  horizontal  lube,  where  they  arc  bent  at  opposite  righl  angles, 

so   that   the   inner  end   of   one   of   them      the    proximal    tube — points   up 


a 


0Z_l 


l~D 


D 


Fig.    58. 


Fig.    59. 


Fig.  58. —  Diagram  to  show  principle  of  Pilot's  tubes  for  measuring  velocity  pulse.  In  both 
tubes  the  fluid  will  rise  because  of  lateral  pressure,  but  in  the  proximal  (left-hand)  tube  it  will 
rise   higher  than   in   the   distal,   because   it  will   also   be   affected    by   the  velocity    of   flow. 

Fig.  59.— Diagram  to  illustrate  the  principle  of  Cybulski's  Photodiematotachometer.  The  fluid 
in  C  stands  higher  than  that  in  D  in  proportion  to  the  velocity  of  flow  of  the  blood  along 
AB. 


Fig.   60. — Dudgeon's  sphygmograph,      (From  Jackson.) 


stream,  and  records  not  only  the  lateral  pressure  but  also  the  pressure 
produced   by   the   sudden   increase   in   velocity   of   the   flow,   while   the 


202  THE    CIRCULATION    OP   THE   BLOOD 

other — the  distal  tube — being  bent  down  stream,  records  merely  lateral 
pressure.  A  photographic  record  of  the  movement  of  the  fluid  in  the 
two  tubes  gives  the  velocity  pulse  (see  Fig.  58).  For  physiologic  pur- 
poses the  form  of  apparatus  used  is  constructed  as  shown  in  Fig.  59. 

Palpable  Pulse. — To  secure  a  record  of  the  palpable  pulse,  the  so- 
called  sphygmograph  is  employed,  although  a  tambour  having  a  button 
in  the  center  which  is  made  to  press  on  the  artery  may  also  be  em- 
ployed. The  commonest  form  of  sphygmograph  is  that  known  as 
Dudgeon's  (Fig.  60).  It  consists  of  a  small  button  connected  with  a 
spring,  the  movements  of  which  are  transmitted  and  magnified  by  means 
of  a  system  of  levers  connected  with  a  writing  point  arranged  so  as 
to  inscribe  its  movements  on  a  moving  surface. 

The  Analysis  of  the  Curve 

The  general  contour  of  the  pulse  waves  taken  by  any  of  the  above 
methods  are  in  general  very  much  the  same.    The  pressure  and  velocity 


Fig.  61. — Pulse  tracing  (sphygmogram)  taken  by  sphygmograph.  a  d,  the  period  of  the  pulse 
curve;  b,  the  primary;  c,  the  dicrotic  wave.  Time  marked  in  fifths  of  a  second.  (From  Prac- 
tical Physiology.) 

pulse  curves  are,  however,  not  usually  taken  for  the  purpose  of  observ- 
ing the  contour  of  the  wave  but  rather  for  measuring  the  difference  in 
pressure  or  velocity  actually  produced  during  each  pulse.  It  is  a  record 
of  the  palpable  pulse  that  is  usually  employed  for  studying  the  contour 
of  the  wave  and  the  presence  of  secondary  waves.  A  record  of  the  pal- 
pable pulse  wave  (Fig.  61)  shows  two  separate  waves  on  the  descending 
limb  of  the  main  wave.  If  a  large  number  of  similar  pulse  curves  are 
taken  from  different  individuals  or  from  the  same  individual  under 
different  conditions,  it  will  be  found  that  of  these  two  waves  the  second 
one  is  by  far  the  more  constant ;  and  if  the  waves  are  timed  in  relation- 
ship to  the  heart  sounds,  this  second  wave  always  occurs  immediately 
after  the  second  sound,  allowance,  of  course,  being  made  for  the  time 
required  for  the  pulse  to  be  transmitted  from  the  heart  to  the  artery 
from  -which  the  pulse  tracing  is  being  taken.  If  the  observation  is 
made  very  carefully,  it  can  indeed  be  shown  that  the  second  sound  cor- 
responds exactly  to  the  notch  which  precedes  this  wave.    The  waves  that 


THE   BLOODFLOW    IN    THE    ARTERIES  203 

precede  this  notch  can  not  be  related  to  definite  changes  occurring  in 
the  heart.  Evidently,  then,  the  secondary  pulse  waves  are  not  all  of 
equal  significance,  by  far  the  most  important  being  that  which  occurs 
immediately  after  the  second  sound,  called  the  dicrotic  wave  (c),  the 
notch  in  front  of  it  being  called  the  dicrotic  notch.  Any  secondary 
waves  occurring  before  the  dicrotic  are  called  predicrotic,  or  if  they 
occur  on  the  ascending  limb  of  the  main  pulse  wave,  as  they  sometimes 
do,  they  are  called  anacrotic.  Waves  occurring  after  the  dicrotic  are 
called  postdicrotic. 

The  relative  importance  of  the  dicrotic,  in  comparison  with  the  pre- 
dicrotic and  postdicrotic  waves,  is  further  evidenced  by  the  fact  that 
it  alone  is  seen  on  a  so-called  hemataugram,  which  is  the  tracing  ob- 
tained by  allowing  a  fine  stream  of  blood,  escaping  from  a  pinhole  made 
in  the  wall  of  an  artery,  to  impinge  upon  a  moving  sheet  of  white  blot- 
ting paper.  That  such  a  tracing  shows  a  dicrotic  but  no  secondary  wave, 
indicates  that  only  the  former  is  present  in  the  blood  stream  itself,  and 
that  the  other  secondary  waves  must  be  produced  by  some  condition 
arising  either  in  the  elastic  tissue  of  the  walls  of  the  blood  vessels,  or 
in  the  elastic  properties  of  the  instruments  used  for  taking  the  pulse 
tracing. 

The  Dicrotic  Wave. — Because  of  its  obviously  greater  significance,  we 
shall  first  of  all  consider  the  exact  cause  of  the  dicrotic  wave  and  of  the 
notch  preceding  it.  Theoretically,  two  possible  causes  might  explain 
the  wave:  either  it  is  due  to  some  secondary  wave  set  up  at  the  heart, 
or  it  is  dependent  upon  waves  reflected  from  the  periphery  of  the  cir- 
culation back  along  the  blood  stream,  just  as  secondary  waves  are  re- 
flected from  the  walls  of  a  tub  of  water  when  a  stone  is  thrown  in  the 
center.  In  considering  this  second  possibility,  we  are  of  course  making 
the  assumption  that  at  the  ends  of  the  arterial  system  there  is  a  sudden 
resistance  to  the  onward  movement  of  blood.  The  frequent  branching 
which  occurs  when  the  arterioles  open  into  the  capillaries  no  doubt  of- 
fers many  opportunities  for  the  reflection  of  pulse  waves  back  to  the 
heart,  but  these  waves  must  be  reflected  at  such  varying  distances  along 
the  arterial  system  that  there  can  be  little  opportunity  for  them  to  be- 
come added  together  so  as  to  form  a  wave  of  sufficient  magnitude  to 
make  itself  .perceptible  in  the  blood  flowing  in  the  larger  arteries.  These 
waves  are  relatively  so  small  and  they  occur  at  such  different  times  that 
the  net  result  of  their  addition,  so  far  as  the  production  of  a  larger 
wave  is  concerned,  must  be  practically  nil.  Notwithstanding  these  con- 
siderations, it  is  possible  that  under  some  conditions,  such  as  in  cases 
of  high  arterial  tension,  certain  of  the  predicrotic  or  postdicrotic  waves 
may  be  due  to  the  above  causes. 


204  THE    CIRCULATION    OF    THE   BLOOD 

That  the  dicrotic  is  not  a  reflected  wave  is  clearly  established  by  the 
fact  that  if  the  distance  between  the  dicrotic  wave  and  the  main  pulse 
wave  is  measured  at  different  points  of  the  arterial  stream,  it  will  al- 
ways be  found  to  be  the  same,  Avhich  obviously  would  not  be  the  case 
were  the  dicrotic  wave  reflected.  If,  for  example,  we  were  to  examine 
the  contour  of  the  wave  produced  by  throwing  a  stone  into  a  tub  of 
water,  Ave  should  find  that  near  the  edge  the  secondary  wave  was  very 
close  to  the  main  wave,  whereas  near  the  center  the  secondary  wave 
would  occur  much  later. 

Our  problem  therefore  narrows  itself  down  to  an  investigation  of 
the  cause  for  the  dicrotic  wave  at  the  central  end  of  the  circulation.  It 
occurs,  as  we  have  seen,  immediately  after  the  beginning  of  diastole. 
That  it  can  not  be  due  to  anything  taking  place  in  the  ventricle  itself  is 
evidenced  by  the  fact  that  such  a  wave  is  absent  from  an  intracardiac 
pressure  curve  (see  page  151),  although  it  is  present  in  the  very  begin- 
ning of  the  aorta.  Now,  the  only  structures  existing  between  those  two 
points  which  could  be  held  responsible  for  this  Avave  are  the  semilunar 
valves — a  conclusion  which  is  sustained  by  the  fact  that,  if  the  aortic 
valves  are  rendered  incompetent  by  hooking  them  back,  or  if  the  pulse 
beat  is  examined  in  patients  suffering  from  an  aortic  insufficiency,  it 
will  be  found  that  the  dicrotic  Avave  is  not  nearly  so  e\Tident  as  usual. 

To  understand  how  the  valves  are  responsible  for  the  production  of  the 
ivave,  the  mechanical  changes  occurring  at  the  root  of  the  aorta  must 
be  clearly  understood  (see  page  155).  The  stretching  of  the  elastic  Avails 
of  the  aorta  Avhich  occurs  with  each  systolic  outrush  of  blood  is  fol- 
loAved  by  a  poAverful  and  sudden  contraction  of  the  stretched  Avails, 
and  the  pressure  thus  brought  to  bear  on  the  column  of  blood  in  the  aorta 
tends  to  impel  it  both  forward  and  backAvard.  The  forward  movement 
adds  itself  to  the  wave  of  increased  pressure  already  produced  by  the 
A-entricular  contraction.  The  backAvard  component  travels  as  far  as  the 
semilunar  valve,  from  which  it  is  reflected,  and  iioav  proceeds  peripher- 
ally along  the  blood  stream  during  the  time  at  which  the  original  pres- 
sure pulse  is  declining.  It  therefore  imprints  itself  on  the  pulse  trac- 
ing as  a  separate  wave,  and  does  so  all  the  more  markedly  when  the 
decline  in  the  main  pulse  Avave  is  rapid,  as  in  cases  in  Avhich  the  periph- 
eral resistance  is  Ioav,  but  fails  to  be  prominent  Avhen,  on  account  of 
a  high  peripheral  resistance,  the  decline  in  the  main  pulse  wave  is  tardy. 
This  explanation  coincides  exactly  with  the  Avell-known  clinical  fact 
that  the  dicrotic  Avave  is  conspicuous  in  pulses  of  Ioav  tension,  but  ill 
marked  or  absent  in  pulses  of  high  tension. 

One  point  remains  to  be  considered,  and  that  is  the  cause  for  the 
sudden  decline  in  the  main  wave  at  the  cessation  of  the  ventricular  out- 


Till:    BL )|'l.o\V    l\    THE    ARTERIES  205 

put,   for,   it    mighl    be   said,   why   should   there   be   SUCh    a    sudden    fall    iii 

pressure  near  the  heart,  whereas  toward  the  periphery,  as  we  have  seen. 
the  pressure  between  the  heartbeats  tends  to  he  maintained  on  account 
of  the  elastic  recoil  of  the  stretched  arterial  walls.  The  explanation 
usually  given  is  that  the  sudden  cessation  of  outflow  of  blood  from  the 
ventricle  a1  the  end  of  the  sphygmic  period  causes  a  negative  pressure 
to  be  produced  in  the  blood  at  the  beginning  of  the  aorta,  thus  tending 
to  cause  a  reflux  of  blood  towards  the  heart,  the  effect  of  which  is  (1)  to 
bulge  the  closed  valves,  and  (2)  to  produce  the  reflected  dicrotic  wave. 
If,  while  fluid  is  flowing  under  pressure  along  a  tube,  the  flow  is  sud- 
denly arrested  by  turning  a  stopcock,  it  is  possible  by  the  use  of  manom- 
eters to  show  that  a  negative  wave  is  set  up  immediately  beyond  the 
stopcock,  and  that  this  negative  wave  travels  along  the  tube  at  a  rale 
depending  on  the  elasticity  of  its  walls. 

Causes  for  Disappearance  of  the  Pulse  in  the  Veins 

The  disappearance  of  the  pulse  in  the  capillaries  and  its  consequent 
absence  in  the  veins  we  have  already  seen  to  be  owing  to  the  combined 
influence  of  the  elasticity  of  the  vessel  walls  and  the  peripheral  resist- 
ance. On  account  of  these  two  factors  the  pressure  conveyed  to  the 
blood  during  systole  is  stored  up  to  be  released  during  diastole  by  the 
recoil  of  the  stretched  vessels.  Sometimes,  however,  the  pulse  gets 
through  to  the  veins,  either  because  the  elasticity  of  the  vessels  is  not  so 
marked,  or  because  the  peripheral  resistance  has  been  lowered  (vaso-, 
dilatation).  In  patients  with  hardened  arteries,  or  in  normal  individu- 
als after  taking  nitrite,  which  dilates  the  peripheral  arterioles,  a  pulse 
may  come  through  at  the  periphery  and  appear  in  the  veins.  This  may 
be  called  the  peripheral  venous  pulse,  and  it  is  to  be  carefully  distin- 
guished from  the  central  venous  pulse  observed  in  the  large  veins,  as 
at  the  root  of  the  neck,  before  any  valves  have  intervened  to  block  the 
transmission  of  the  auricular  pressure  wave  back  into  the  column  of 
blood  in  the  veins.  If  a  pulse  is  seen  in  a  large  vein  and  there  is 
doubt  as  to  whether  it  is  peripheral  or  central  in  origin,  this  doubt  can 
be  immediately  removed  by  locally  constricting  the  vein;  if  the  pulse 
is  peripheral,  it  will  disappear  on  the  heart  side  of  the  constriction;  if 
it  is  central,  on  the  side  away  from  the  heart. 


CHAPTER  XXIV 

THE  RATE  OF  MOVEMENT  OF  THE  BLOOD  IN  THE 
BLOOD  VESSELS 

Since  the  object  of  the  circulation  is  to  maintain  an  adequate  move- 
ment of  blood  in  the  tissues  and  capillaries,  it  is  evident  that  besides 
measuring  the  pressure  of  bloodflow,  we  should  also  measure  the  rate 
of  its  movement,  or,  as  it  is  often  called,  the  mean  velocity.  This  measure- 
ment may  be  undertaken  either  for  a  given  vessel  or  for  a  complete 
vascular  area,  such,  for  example,  as  that  of  one  of  the  viscera  or  one 
of  the  extremities — the  mass  movement  of  the  blood.  Or  instead  of 
measuring  the  mean  velocity  we  may  desire  to  know  how  long  it  takes 
for  a  particle  of  blood  to  traverse  a  given  vascular  area.  Such  a  meas- 
urement is  called  the  circulation  time;  it  does  not  at  all  tell  us  how  long 
it  takes  for  all  the  blood  to  pass  through  the  given  area,  but  only,  as 
stated,  the  time  required  for  the  circulation  of  a  fraction  of  the  blood 
through  a  particular  field. 

VELOCITY  OF  FLOW  IN  A  VESSEL 

Special  methods  have  been  devised  for  the  measurement  of  each  of 
these  three  velocities.  For  the  measurement  of  the  velocity  of  flow 
through  a  main  artery  or  vein,  methods  similar  to  those  employed  by 
hydraulic  engineers  are  employed ;  that  is  to  .say,  the  volume  of  blood, 
in  cubic  centimeters,  which  passes  a  given  point  is  measured  for  a 
given  time,  and  the  result  divided  by  the  cross  section  of  the  vessel  at 
the  point  of  observation.  The  result  gives  us  the  mean  lineal  velocity. 
To  measure  the  outflow  of  blood  in  a  given  time,  the  simplest  method 
would  be  to  cut  across  the  vessel  and  collect  the  blood  in  a  graduate, 
but  obviously  in  this  method  an  error  would  be  introduced,  because 
cutting  the  vessel  would  lower  the  peripheral  resistance  and  remove  the 
natural  obstruction  to  the  flow  present  in  the  intact  animal.  Moreover, 
the  hemorrhage  would  in  itself  introduce  a  disturbing  factor  on  account 
of  the  loss  of  circulating  fluid. 

To  make  such  measurements  of  any  value,  it  is  obviously  necessary  to 
retain  the  peripheral  resistance.  For  smaller  vessels  this  can  be  done 
by  introducing  in  the  course  of  the  artery  a  long  glass  tube  bent  in  the 

206 


RATIO   OP    MOVEMENT   OF    THE    BLOOD 


207 


shape  of  the  letter  II  (Fig.  62),  or  by  merely  allowing  the  vessel  to 
bleed  into  a  graduated  lube  and  seeing  how  long  the  blood  column  takes 
to  travel  from  one  end  to  the  other.  This  method  is  of  considerable 
value  in  measuring  the  velocity  of  flow  from  small  vessels  such  as  the 
veins  coming  from  glands  and  muscles.  For  larger  vessels  a  so-called 
stromuhr  is  employed.  There  are  numerous  forms  of  stromuhr;  that 
shown  in  the  diagram  (Ludwig's)  (Fig.  62)  consists  of  two  glass  bulbs 
united  above,  and  connected  below  with  tubes  that  open  flush  with  the 
surface  of  a  brass  disc.  This  is  pivoted  at  its  center  with  another  similar 
platform  also  having  flush  with  the  surface  the  openings  of  two  tubes  con- 
nected with  the  cut  ends  of  the  artery  or  vein.  In  a  certain  position  of 
the  platform,  the  tubes  from  the  artery  or  vein  are  exactly  opposite 
those  of  the  bulbs,  so  that  the  blood  can  flow  from  one  end  of  the  vessel 


Fig.    62. — Forms   of   apparatus   for   measurement   of  blood   velocities. 

/.  Volkmann's  hemodromometer.  The  blood  vessel  is  attached  to  the  two  short  side  tubes, 
and  according  to  the  position  cf  the  stopcock,  the  blood  flows  either  directly  between  them  or 
through   the   U-shaped   glass  tube. 

2.  Ludwig's  stromuhr.  The  tubes  on  the  lower  end  of  each  of  the  two  glass  bulbs  pierce 
a  circular  brass  platform  and  end  flush  with  its  surface.  This  platform  pivots  at  its  center  on 
a  similar  lower  platform  with  two  openings  connected  with  the  tubes  that  lead  to  the  blood 
vessel. 


through  the  bulbs  to  the  other  end.  To  use  the  instrument  the  proxi- 
mal bulb  is  filled  with  oil  and  the  peripheral  one  with  physiologic  saline. 
The  clip  is  then  removed  from  the  central  end  of  the  artery,  and  the  blood 
flows  in  and  displaces  the  oil,  which  in  turn  displaces  the  saline  in  the 
peripheral  end  of  the  artery.  When  the  blood  has  risen  to  a  mark  on 
the  tube  joining  the  two  bulbs,  the  instrument  is  rapidly  rotated  so  that 
the  oil  is  brought  back  again  into  the  proximal  position,  the  rotation 
being  effected  so  quickly  that  there  is  no  distinct  interruption  in  blood- 
flow.  The  operation  is  repeated  in  this  way  for  a  given  period  of  time. 
Counting  accurately  the  number  of  revolutions,  then  multiplying  the 
number  of  revolutions  by  the  capacity  of  the  bulbs,  we  get  in  cubic 


208  TITE    CIRCULATION    OF    THE    151,000 

centimeters  the  amount  of  blood  that  has  flowed  through  the  instrument 
in  a  definite  unit  of  time.  This  gives  us  the  volume  flow  and,  if  the 
result  is  divided  by  the  cross  section  of  the  vessel  in  square  centimeters, 
Ave  obtain  what  is  known  as  1hc  mean  lineal  velocity.  Many  modifica- 
tions have  been  made  of  this  instrument,  but  it  is  unnecessary  to  go  into 
them  here. 

The  general  result  of  such  measurements  has  been  to  show  that  the 
lineal  velocity  is  inversely  proportional  to  the  cross  section  of  the  vesjsel 
at  the  point  'of  observation.  It  is  obvious  that  the  volume  of  blood 
flowing  out  of  the  heart  to  the  aorta  in  a  given  time  is  exactly  equal 
to  that  flowing  into  it  by  the  vena  cava,  and  likewise  that  the  volume 
flowing  into  an  organ  is  exactly  equal  to  that  which  flows  out.  Conse- 
quently the  lineal  velocity  will  be  inversely  proportional  to  the  sec- 
tional area  of  the  vessel.  The  principle  is  the  same  as  that  which  gov- 
erns the  velocity  of  flow  of  a  stream:  when  the  bed  is  narrow,  the  cur- 
rent is  swift,  but  it  becomes  sluggish  when  the  bed  is  wide.  If  the 
arteries  were  of  the  same  caliber  as  the  veins,  the  mean  velocity  of  the 
bloodflow  through  the  two  would  be  the  same,  but  actually  it  is  much 
greater  in  the  arteries  because  the  lumen  of  these  at  a  given  point  in  the 
circulation  is  only  from  one-third  to  one-half  that  of  the  corresponding 
vein. 

It  must  be  understood  that  we  are  dealing  above  with  the  mean 
velocity  in  a  unit  of  time,  and  that  there  must  be  considerable  alteration 
with  each  systole  and  diastole,  constituting  the  velocity  pulse  (page  200). 
The  degree  of  this  alteration  with  each  velocity  pulse  is  much  less  at 
the  periphery  of  the  circulation  than  near  the  heart.  As  the  periphery 
is  reached,  the  flow  becomes  more  uniform.  It  must  further  be  re- 
membered that,  although  the  mean  velocity  depends  essentially  upon 
the  area  of  the  vascular  bed,  yet  it  is  subject  to  considerable  variations 
as  a  result  of  changes  either  in  the  force  or  rate  of  the  heartbeat  or 
in  the  facility  of  outflow  from  the  ends  of  the  arterial  system — that  is, 
changes  in  peripheral  resistance. 

It  is  usually  stated  that  the  mean  lineal  velocity  in  the  carotid  artery 
is  about  300  millimeters  per  second;  and  in  the  jugular  vein,  about  150 
millimeters;  whereas  in  the  capillaries,  where  the  total  area  of  the 
vascular  bed  has  become  enormously  increased,  being  perhaps  some  800 
times  that  of  the  aorta,  the  velocity  of  flow  is  only  about  half  a  milli- 
meter per  second. 

MASS  MOVEMENT  OF  THE  BLOOD  IN  A  VASCULAR  AREA 

Methods. — In  considering  the  bloodflow  or  mass  movement  of  the  blood 
in  the   different  regions   of  the   body,   it  is  usually  more   practical  to 


RATE   OF    MOVEMENT   OF    THE    BLOOD  209 

measure,  not  the  mean  lineal  velocity  of  Hie  inflowing  and  out  (lowing 
blood,  but  rather  how  many  cubic  centimeters  of  Mood  are  traversing 
the  pari  per  100  grams  of  organ  or  tissue  per  unit  of  time.  Such  meas- 
urements may  be  made  in  a  variety  of  ways.  Tf  there  are  hut  one  artery 
and  one  vein  to  the  part,  the  stromuhr  may  of  course  he  employed,  and 
it  may  he  inserted  in  either  the  arterial  or  the  venous  circuit.  For 
measuring  the  mass  movement  of  blood  through  such,  large  viscera  as 
the  liver,  this  is  indeed  the  only  method  that  can  be  employed,  the 
stromuhr  being  inserted  either  in  the  course  of  the  portal  vein  and  he- 
patic arteries,  or,  better  still,  in  the  vena  cava  just  below  the  openings 
of  the  hepatie  vein,  the  vena  cava  being  shut  off  for  a  moment  between 
the  liver  and  the  heart  and  the  blood,  as  it  flows  from  the  hepatic  vein, 
allowed  to  collect  in  the  stromuhr.  For  other  organs  and  tissues,  how- 
ever, methods  which  do  not  involve  any  interference  with  the  blood 
vessels  may  be  employed.  One  of  these  is  the  so-called  pletJiysmographic 
method  of  Brodie.  An  organ,  such  as  the  kidney,  is  enclosed  in  a  plethys- 
mograph  (see  page  230,)  and  while  a  record  of  its  volume  is  being 
inscribed  on  a  quickly  revolving  drum,  the  vein  is  suddenly  clamped, 
with  the  result  that  the  kidney  volume  expands  in  proportion  to  the 
mass  of  blood  flowing  into  it.  When  the  expansion  has  reached  a  cer- 
tain degree,  the  clamp  is  removed  and  the  bloodflow  allowed  to  pur- 
sue its  course.  It  is  then  an  easy  matter,  by  graduating  the  plethys- 
mograph,  to  determine  how  many  cubic  centimeters  of  blood  must  have 
flowed  into  the  organ  in  the  given  time.  To  avoid  serious  local  asphyxia 
in  the  tissue,  the  clamp  must  be  applied  to  the  vein  for  only  the  briefest 
period  of  time.  This  method  may  also  be  employed  for  measuring  the 
bloodflow  through  the  extremities.  Thus,  if  the  arm  is  enclosed  in  the 
plethysmograph  (Fig.  63)  and  a  band  encircling  the  arm  above  the 
plethysmograph  is  tightened  so  as  to  constrict  the  veins  but  not  the  ar- 
teries, the  rate  at  which  the  volume  of  the  arm  within  the  plethysmograph 
expands  will  correspond  to  the  rate  at  which  blood  is  flowing  into  it 
(Hewlett). 

For  the  purpose  of  measuring  blood  flow  through  the  upper  or  lower 
extremities,  a  much  more  serviceable  clinical  method  is  that  of  G.  N. 
Stewart.  This  depends  on  the  principle  that,  provided  the  blood  passing 
from  the  thorax  to  the  hands  or  feet  is  of  constant  temperature,  the 
rate  at  which  heat  is  dissipated  from  the  hands  or  feet  will  be  directly 
proportional  to  the  rate  of  movement  of  the  blood  through  these  parts. 
Fortunately  for  the  method,  the  hands  particularly,  but  also  the  feet, 
are  more  or  less  perfect  radiators — at  least  they  are  to  this  extent,  that 
if  the  temperature  in  their  environment  is  not  much  lower  than  the 
temperature  of  the  blood,  then  while  this  is  traversing  the  part,  it  will 


210 


THE    CIRCULATION    OP    THE    BLOOD 


lose  heat  to  the  environment  until  the  outflowing  or  venous  blood  is  at 
exactly  the  same  temperature  as  the  environment;  for  example,  if  the 
hand  is  placed  in  water  that  is  a  little  cooler  than  that  of  the  blood, 
and  the  temperature  of  the  blood  in  one  of  the  large  veins  of  the  hand 
is  measured,  it  will  be  found  to  be  the  same  as  that  of  the  water  in  the 
water-bath. 

To  measure  the  rate  of  flow,  therefore,  we  must  ascertain:  (1)  how 
much  heat  has  been  given  out  by  the  part  to  the  water  surrounding  it 
in  a  given  time,  and  (2)  the  difference  in  temperature  of  the  inflowing 
(arterial)   and  outflowing  (venous)   blood.     We  measure  the  amount  of 


Fig.  63. — Plethysmograph  for  recording  volume  changes  in  the  hand  and  forearm.  By  observ- 
ing the  rate  with  which  the  volume  increases  when  the  arm  is  compressed,  the  mass  movement  of 
the   blood   can   be   determined.      (From  Jackson.) 

heat  given  out  to  the  water  in  calories,  a  calorie  being  the  amount  of 
heat  required  to  raise  the  temperature  of  1  c.c.  of  water  from  0°  C. 
to  1°  C.  Suppose,  for  example,  a  hand  were  placed  in  3,000  c.c.  of 
water  at  33°  C,  and  that  after  ten  minutes  the  temperature  had  risen 
to  33.5°  C,  then  the  amount  of  calories  given  out  would  be  3,000  x  0.5= 
1500.  Since  calories  equal  cubic  centimeters  multiplied  by  change  in 
temperature,  it  follows  that  if  we  divide  the  figure  representing  them  by 
the  actually  observed  difference  in  temperature  between  inflowing  and 
outflowing  blood,  the  result  must  equal  the  number  of  cubic  centimeters 
of  blood  that  has  flowed  through  the  part.  The  temperature  of  the  in- 
flowing blood  has  been  found  to  be  practically  identical  with  that  of  the 


RATH   OK    MOVEMENT   OF    THE    BLOOD  211 

mouth  under  the  tongue;  whereas  of  course  the  temperature  of  the  venous 

blood,  as  already  explained,  is  equal  to  the  mean  temperature  of  the 
water  during  the  time  that  the  hand  was  immersed  in  it.  Further  de- 
tails of  the  technic  of  this  method  will  be  found  elsewhere,  but  it  may  be 

said  here  that  il  is  extremely  simple  and  accurate,  and  that  it  requires 
nothing  more  than  (1)  an  accurate  thermometer  ranging  between  abo,,J 
40°  C.  and  50°  C,  with  a  scale  so  drawn  out  that  readings  can  he  made 
to  Moo  of  a  degree,  and  (2)  a  well-constructed  vessel  of  about  3,000 
e.e.  capacity,  with  double  walls,  the  space  between  them  being  packed 
with  some  heat-insulating  material  such  as  ground  cork. 

Results. — Regarding  the  results  obtained  with  these  methods,  it  has 
been  found  that  the  blood  supply  for  eaeh  100  grams  of  tissue  in  the 
viscera,  as  measured  by  the  stromuhr  method,  is  about  as  follows:  stomach, 
21  e.e.;  intestine,  71  e.e.;  spleen,  58  e.e.;  liver,  arterial,  25  e.e.;  liver, 
venous,  59  e.e.;  liver,  total,  84  e.e.;  brain,  136  e.e.;  kidney,  150  e.e.;  thy- 
roid gland,  560  e.e.  The  large  blood  supplies  of  the  thyroid  gland  and 
of  the  kidney  are  the  most  striking  results  of  these  observations. 

By  the  use  of  the  calorimeter  method  the  bloodflow  through  the  hands 
and  feet  of  a  healthy  young  man  has  been  found  to  be  about  13  grams 
per  100  c.c.  of  hand  per  minute  for  the  right  hand,  and  about  half  a 
gram  less  for  the  left.  The  footflow  is  only  about  one-third  to  one-half 
that  of  the  hand  per  100  c.c.  of  tissue — a  difference  which  is  largely 
owing  to  the  greater  proportion  of  skin  and  the  smaller  proportion  of 
bone  in  the  hand.  The  average  footflow  or  handflow  for  a  given  indi- 
vidual under  ordinary  conditions  is  remarkably  constant  from  time  to  time, 
but  it  is  extraordinarily  sensitive  to  changes  in  the  temperature  of  the 
environment  in  which  the  subject  has  been  living  for  some  time  previous 
to  the  measurement.  In  one  individual,  when  the  room  temperature  was 
20°  C,  the  flow  in  the  right  hand,  expressed  in  grams  of  blood  per  100 
c.c.  of  hand  or  foot,  was  10.1;  when  it  was  22.8°  C,  the  flow  was  12.8; 
when  it  was  25°  C,  12.1 ;  when  it  was  30°  C,  18.5.  On  account  of  the 
influence  of  temperature  on  the  flow,  it  is  extremely  important  that  the 
measurements  should  be  made  in  a  small  room  the  temperature  of  which 
is  kept  constant,  or  if  it  must  be  made  in  the  wards,  the  bed  should  be  sur- 
rounded by  curtains.  The  measurements  made  on  the  hands  of  dispensary 
patients  shortly  after  coming  in  from  outside  air  are  very  likely  to  be 
fallacious.  The  importance  of  making  such  bloodflow  measurements  in 
the  clinic  will  be  alluded  to  later. 

Of  course  the  measurements  made  by  the  above  method  in  man  tell  us 
only  the  rate  of  flow  in  the  periphery  of  the  body,  and  furnish  us  with  no  in- 
formation regarding  the  flow  of  blood  through  the  viscera.  It  is,  how- 
ever, a  well-established  fact  that  the  bloodflow  in  the  central  part  of  the 


212  THE    CIRCULATION    OF    THE    BLOOD 

circulation  is  more  or  less  reciprocal  with  that  at  the  periphery,  an 
increase  in  the  one  place  being  accompanied  by  a  corresponding  de- 
crease in  the  other. 

The  Visceral  Bloodflow  In  Man 

The  visceral  bloodflow  in  man  can  be  measured  indirectly  in  the  case 
of  the  lungs,  either,  (1)  by  finding  the  quantity  of  oxygen  absorbed  by  the 
blood  during  an  interval  of  time  that  is  less  than  that  required  for  the 
blood  to  travel  once  round  the  circulation  (60  seconds)  and  comparing 
this  with  the  oxygen  content  of  samples  of  arterial  and  venous  blood,  or  (2) 
by  causing  a  person  to  breathe  a  known  quantity  of  nitrous-oxide  gas  and 
then  finding  the  concentration  of  this  gas  in  the  blood  after  leaving  the 
lungs.  In  the  former  method  the  difference  in  oxygen  percentage  be- 
tween arterial  and  venous  blood  will  be  less  for  a  given  absorption  of 
oxygen  from  the  alveoli  the  more  rapid  the  circulation  of  blood  through 
the  lungs,  and  in  the  latter  method  for  the  absorption  of  a  given  amount 
of  nitrous  oxide,  the  less  will  be  the  concentration  of  this  gas  in  the 
Id ood  the  more  rapid  the  circulation.  Obviously  these  estimations  must 
be  made  only  over  periods  of  time,  less  than  that  taken  for  any  of 
the  blood  to  complete  one  circuit  of  the  circulation. 

The  methods  are  admittedly  only  approximate,  but  the  results  are  of 
much  interest,  mainly  because  of  the  indication  they  give  us  as  to  the 
amount  of  blood  pumped  out  by  the  ventricle  with  each  heartbeat,  or 
during  a  given  period  of  time.  The  results  have  been  found  to  vary 
considerably;  thus,  one  author  (Krogh)  places  the  output  of  blood  per 
minute  as  between  2.3  and  8.7  liters,  which  would  correspond,  at  a 
pulse  rate  of  70,  to  an  output  per  heartbreat  of  from  40  to  120  c.c.  An 
immediate  and  very  marked  increase  has  been  found  to  occur  during 
muscular  work.  By  comparing  the  bloodflow  through  the  hand  with 
that  through  the  lungs,  an  estimate  can  be  formed  in  a  given  individual 
as  to  the  relative  magnitude  of  the  peripheral  and  visceral  moieties  of 
blood.  Interesting  results,  which  will  be  referred  to  later,  have  been 
obtained  from  such  measurements. 

The  Work  of  the  Heart 

Meanwhile  it  is  of  interest  to  note  that  we  may  calculate  from  the 
ventricular  output  of  the  blood  the  amount  of  work  that  the  heart  is  doing 
in  maintaining  the  circulation.  Of  course  the  calculation  is  again  only 
approximate,  since  we  have  to  assume  certain  figures.  If  we  assume  that 
in  a  70-kilogram  man  the  quantity  of  blood  is  4,200  c.c.  (see  page  85), 
and  that  it  takes  about  one  minute  for  all  the  blood  to  complete  a  cir- 
culation, then  the  work  performed  by  the  left  ventricle  in  one  minute 


RATE   OF    MOVEMENT   OF   THE   BLOOD  213 

will  be  equal  to  thai  done  in  raising  the  above  quantity  of  blood  to  a 
heighl  corresponding  to  the  mean  pressure  in  the  aorta.  If  we  take  this 
pressure  as  130  millimeters  of  mercury,  which  would  correspond  to  a 
column  of  Mood  1,755  meters  high  (13.5x130=1755  mm.  blood,  or  1.755 
meter),  the  work  done  by  the  left  ventricle  would  be  1.755x4.2=7.37 
kilogram-meters  in  one  minute,  or  in  twenty-four  hours  roughly  about 
10()()0  kilogram-meters.  The  work  done  by  the  right  ventricle  is  probably 
about  one-third  that  of  the  left,  this  being  about  the  ratio  of  the  pres- 
sures in  the  two  chambers.  The  total  work  of  the  two  ventricles  is  there- 
fore about  14000  kilogram-meters.  This  represents  an  enormous  amount 
of  work:  indeed  il  has  been  computed  that  it  is  sufficient  to  raise  a  man 
<>!'  70  kilograms  to  about  twice  the  height  of  the  highest  skyscraper  in 
New  York.  The  work  thus  expended  in  forcing  the  blood  through  the 
capillaries  becomes  converted  by  friction  in  the  small  blood  vessels  into 
heat,  the  heat  equivalent  of  the  above  amount  of  work  being  roughly 
about  350  calories  (see  page  537). 

THE  CIRCULATION  TIME 

The  circulation  time,  or  the  time  taken  by  a  drop  of  blood  to  travel 
between  two  points  in  the  circulation,  can  be  determined  in  laboratory 
animals  by  a  variety  of  methods,  all  depending  on  the  principle  of  seeing 
how  long  it  takes  for  a  drop  of  some  substance  injected  into  an  artery  to 
appear  in  the  corresponding  vein.  For  example,  to  determine  the  time 
taken  for  a  drop  of  blood  to  pass  from  the  jugular  vein  into  the  carotid 
artery  in  a  rabbit,  a  solution  of  methylene  blue  in  isotonic  saline  is  in- 
jected into  the  former  vessel  and  the  moment  of  its  appearance  through 
the  Avails  of  the  artery  determined  by  a  stop-wratch.  If  the  walls  are  too 
thick  to  admit  of  the  employment  of  this  method,  a  strong  solution  of 
sodium  chloride  may  be  substituted  for  the  methylene  blue,  and  the  mo- 
ment of  its  appearance  at  another  point  of  the  circulation  determined  by 
observing  the  electrical  conductivity  of  the  vessel.  Since  the  con- 
ductivity of  a  blood  vessel  depends  partly  on  the  concentration  of  elec- 
trolytes in  the  blood  flowing  through  it,  the  moment  at  which  the  salt 
solution  appears  will  be  indicated  by  a  change  in  electrical  resistance 
(G.  N.  Stewart). 

By  such  methods,  it  has  been  found  that  the  time  for  the  pulmonary 
circulation  is  very  short  compared  with  that  of  the  systemic  circulation. 
In  a  rabbit  it  is  usually  a  little  less  than  four  seconds;  in  an  average- 
sized  dog  of  about  12  kilograms,  it  is  about  eight  seconds;  and  in  man 
it  is  computed  to  be  about  fifteen  seconds.  On  the  other  hand,  the  cir- 
culation time  in  such  viscera  as  the  spleen  and  kidney  is  relatively  long, 


214  THE    CIRCULATION    OF    THE   BLOOD 

and  more  susceptible  than  that  of  the  lungs  to  different  conditions  of 
temperature.  In  a  dog  in  which  the  pulmonary  circulation  time  was 
about  8.5  seconds,  that  of  the  spleen  was  about  11  seconds,  and  of  the 
kidney  about  17.5  seconds.  The  shortest  circulation  time  of  all  is  of 
course  that  in  the  coronary  artery,  but  that  through  the  retina  can  not  fall 
far  behind  it. 

To  determine  the  total  circulation  time,  we  must  know:  (1)  the  average 
amount  of  blood  passing  by  each  part  in  a  given  time,  and  (2)  the  average 
circulation  time  of  each  part.  From  such  computations,  which  however 
are  obviously  subject  to  considerable  error,  it  has  been  reckoned  that  the 
total  circulation  time  in  man  must  lie  somewhere  between  1  and  1.25 
minutes. 

MOVEMENT  OF  BLOOD  IN  VEINS 

Before  leaving  this  part  of  our  subject,  a  few  words  may  be  said  con- 
cerning the  forces  concerned  in  the  movement  of  blood  in  the  veins  from 
the  capillaries  to  the  heart.  By  the  time  that  the  venules  are  reached, 
owing  to  friction  in  the  capillaries  the  blood  will  have  lost  most  of  the 
force  imparted  to  it  by  the  heart  action.  Nevertheless,  this  remaining 
vis  a  tergo  must  be  considered  as  the  basic  cause  for  the  movement  of 
the  venous  blood  near  the  periphery.  As  the  venules  get  larger,  two 
other  factors  come  into  play:  the  massaging  influence  of  the  muscles, 
and  the  valves  of  the  veins.  By  the  movements  of  the  muscles  the  veins 
which  lie  between  will  be  rhythmically  compressed,  and  this  will  tend  to 
cause  the  blood  to  be  moved  forward  and  backward  in  them,  the  back- 
ward movement  being  however  prevented  by  the  operation  of  the  valves. 
When  the  tonicity  of  the  muscles  is  subnormal,  as  in  conditions  of  ill 
health,  the  absence  of  this  massaging  action  permits  the  blood  to  stag- 
nate in  the  veins,  especially  in  those  of  the  lower  extremities  in  upright 
animals,  with  the  consequence  that  the  veins  become  dilated,  particularly 
just  above  the  valves,  thus  causing  the  condition  known  as  varicose  veins. 

As  the  thorax  is  approached,  two  other  factors  become  operative:  the 
aspirating  influence  of  the  thorax  during  inspiration,  and  the  negative 
intraventricular  pressure  (see  page  152).  There  is  no  doubt  that  the 
former  of  these  is  of  considerable  importance  in  maintaining  the  venous 
return  near  the  heart,  for  although  the  change  of  pressure  induced  by  in- 
spiration amounts  to  only  5  millimeters  of  mercury,  yet  it  acts  so 
slowly  that  it  produces  a  considerable  influence.  The  aspirating  effect 
of  the  ventricle  at  the  beginning  of  diastole  is,  however,  of  no  sig- 
nificance in  attracting  blood  to  the  heart,  for  although,  as  we  have  seen, 
it  may  be  considerable,  yet  it  lasts  for  so  short  a  time  that  it  could  not 


RATE  OF    MOVEMENT  OF   THE    BLOOD  215 

overcome  the  inertia  of  the  column  of  blood  in  the  vena  cava.  Even  if 
the  negative  pressure  did  last   Eor  a  longer  period,  it  could  not  attract 

more  than  a  small  amount  of  blood,  because  it  would  cause  the- thin 
collapsible  walls  of  the  veins  to  come  together  and  thus  block  the  pas- 
sage towards  the  heart. 


CHAPTER  XXV 

THE  CONTROL  OF  THE  CIRCULATION 

The  available  blood  in  the  body  is  parceled  out  to  the  various  organs 
and  tissues  according  to  their  relative  activities,  and,  since  these  vary 
from  time  to  time,  the  question  arises  as  to  the  nature  of  the  mechanism 
or  mechanisms  involved  in  bringing  about  this  adjustment.  Two  possible 
methods  of  increasing  the  supply  are:  an  increase  in  the  mass  movement 
of  all  the  blood  in  circulation,  and  a  reciprocal  adjustment  of  the  resistance 
to  the  flow  in  different  vascular  areas  brought  about  by  vasodilatation 
in  one  and  vasoconstriction  in  others.  Both  of  these  methods  might 
operate  together. 

Two  agencies  can  be  thought  of  as  responsible  for  bringing  about 
the  above  changes:  (1)  chemical  substances  or  hormones,  present  in 
the  blood,  and  (2)  the  nervous  system. 

The  influence  of  chemical  substances,  or  hormones,  (page  729)  in  the 
control  of  the  circulation  is  undoubtedly  an  important  one,  and  of  those 
known  at  the  present  time  two  groups  may  be  mentioned:  (1)  sub- 
stances which  alter  the  hydrogen-ion  concentration  of  the  blood,  and 
(2)  so-called  pressor  and  depressor  substances,  produced  either  by  duct- 
less glands,  such  as  the  adrenal,  or  by  the  activity  of  tissues.  An  in- 
crease in  hydrogen-ion  concentration  of  the  blood  not  only  affects  the 
heartbeat  (see  page  168),  but  causes  a  marked  dilatation  of  the  blood 
vessels,  so  that  both  the  central  and  the  peripheral  changes  will  be  such 
as  to  encourage  an  increased  flow  of  blood  through  the  active  organs 
or  viscus.  Thus,  during  muscular  activity  of  the  leg  muscles  there  will 
be  a  tendency  to  an  increase  in  the  hydrogen-ion  concentration  of  the 
blood  as  a  whole,  resulting  in  a  greater  cardiac  activity  and  a  greater 
outrush  of  blood  through  the  aorta,  and  at  the  same  time  the  vessels  of 
the  acting  muscle  will  have  become  especially  dilated  because  of  the 
production  by  the  active  muscles  either  of  lactic  acid  or  of  carbonic  acid. 
The  active  muscle  also  produces  such  substances  as  imidazole,  which 
have  a  powerful  vasodilating  action.  Such  substances  are  sometimes 
called  depressor. 

Though  the  hormone  control  of  the  circulation  is-  undoubtedly  of  great 
importance,  it  is  probably  much  less  so  than  that  exercised  through  the 
nervous  system,  and  here  again  the  control  is  centered  partly  in  the 

216  •    . 


THE   CONTROL   OF   THE   CIRCULATION  217 

heart  and  partly  in  the  peripheral  resistance.  The  nerve  control  of  the 
heart  is  effected  through  the  vagus  and  sympathetic  nerves,  and  thai 
exercised  on  the  blood  vessels,  through  the  so-called  vasoconstrictor  and 
vasodilator  nerves. 

The  activity  of  the  nerve  centers  from  which  the  cardiac  and  vaso- 
motor impulses  are  discharged  is  controlled  by  afferent  impulses  com- 
ing from  the  various  regions  of  the  body.  When  a  gland  becomes  more 
active,  we  must  suppose  that  stimulation  of  the  sensory  fibers  has  caused 
afferent  impulses  to  be  transmitted  to  the  cardiac  and  vasomotor  centers, 
upon  which  they  act  in  such  a  way  as  to  produce  increased  heart  ac- 
tion and  a  local  dilatation  of  the  blood  vessels  of  the  active  gland,  with 
perhaps  a  constriction  of  the  blood  vessels  of  the  rest  of  the  body. 

THE  NERVE  CONTROL  OF  THE  HEARTBEAT 

The  Vagus  Control 

Willi  regard  to  the  control  exercised  through  the  vagus  nerve,  we  have 
already  seen  that  the  cutting  of  the  two  nerves  in  the  neck  causes  the 
heart  to  quicken  and  the  arterial  blood  pressure  to  rise,  whereas  a 
stimulation  of  the  peripheral  end  of  the  nerve  causes  the  heart  to  be- 
come slowed,  if  not  stopped  altogether,  and  the  blood  pressure  to  fall. 

For  the  more  detailed  investigation  of  the  nature  of  the  vagus  control 
of  the  heart,  it  is  necessary  to  observe  the  exposed  heart  itself — an  ex- 
periment which,  for  obvious  reasons,  can  be  most  simply  performed  in 
a  cold-blooded  animal,  such  as  the  frog  or  turtle,  but  which  can  also 
be  performed  in  mammals  provided  artificial  respiration  is  maintained. 
The  general  effect  of  the  vagus  in  both  groups  of  animals  is  the  same, 
although  apparent  differences  may  exist  on  account  of  the  relative  im- 
portance of  the  different  parts  of  the  heart  in  the  origination  and  propa- 
gation of  the  heartbeat. 

The  Cold-Blooded  Heart. — If  the  vagus  nerve  on  the  right  side  in  the 
turtle  (the  left  nerve  is  inactive  in  this  animal)  is  stimulated  with  a 
very  feeble  electric  current,  while  simultaneous  records  are  being  taken 
of  the  contractions  of  the  auricles  and  ventricles  in  the  manner  shown 
in  the  accompanying  tracing  (Fig.  64),  it  will  often  be  found  that  there 
is  a  weakening  of  the  auricular  beats  without  any  change  in  those  of 
the  ventricle.  If  the  strength  of  stimulus  is  somewhat  increased,  the 
auricular  beat,  besides  becoming  weaker,  will  also  become  slower,  but 
meanwhile  the  ventricular,  although  also  slower,  may  become  distinctly 
stronger.  At  first  sight  this  result  may  be  a  little  confusing,  because 
it  would  seem  to  indicate  that  the  vagus  nerve  weakens  the  auricular, 


218  THE    CIRCULATION    OF    THE   BLOOD 

but  strengthens  the  ventricular  beat.  It  is  clear,  however,  that  the 
strengthening  of  the  ventricular  beat  is  merely  due  to  the  fact  that  the 
cavity  has  become  better  filled  with  blood  during  diastole  as  a  result  of 
the  slowing  of  the  auricle.  These  results  indicate,  then,  that  with  weak 
stimulation  the  vagus  exerts  its  direct  influence  only  on  the  auricle.    If 


Fig.  64. — Simultaneous  tracings  from  auricle  and  ventricle  of  turtle's  heart.  Between  the  crosses 
the  vagus  was  stimulated,  with  the  effect  that  the  auricular  beat  diminished  in  force  but  not  in 
frequency,    while    the    ventricular    beats    were    practically    unaffected.      (From    Howell's    Physiology.) 

the  stimulation  is  strong  enough  both  auricles  and  ventricles  cease  to 
beat  altogether,  and  if  the  stimulus  is  maintained,  the  inhibition  may  go 
on  for  a  very  long  time  (Fig.  65). 

Usually,  even  though  the  stimulus  is  maintained  the  heart  begins  to 


Fig.    65. — Effect    of   vagus    stimulation    on    heart    of    turtle.      Note    the    after    effect    of    augmentation. 

beat  again  after  a  time,  at  first  only  occasionally  but  gradually  more 
rapidly.  This  is  known  as  escapement,  and  it  indicates  that  the  energy 
pent  up  in  the  heart  during  the  vagus  inhibition  has  at  last  overcome 
the  inhibiting  influence  of  the  nerve,  which  is  meanwhile  becoming 
fatigued.  All  of  these  results  could  be  quite  satisfactorily  explained  on 
the  assumption  that  the  action  of  the  vagus  is  confined  to  the  sinus, 


Till)    CONTROL.    OF    Till;    CIRCCLATION 


219 


which,  it   will  be  remembered,  dominates  ihe  beat  in  the  rest  of  the 

heart.  There  is  evidence,  however,  that  the  vagUS  also  directly  affects 
the  rhythm  of  the  ventricle.  It  may  be  stated  as  a  general  conclusion 
from  these  results  that  the  influence  of  the  vagus  upon  the  heartbeat  is 
chit  jhi  a  ni<  red  upon  those  parts  of  the  organ  in  which  the  rhythmic  power 
is  must  highly  developed. 

Besides  affecting  the  rate  and  strength  of  the  heartbeat,  the  vagus  also 
exercises  a  control  on  the  conductivity  of  the  cardiac  muscle.  Thus,  if 
a  partial  block  is  instituted  in  the  turtle  heart  by  applying  a  clamp  be- 
tween the  auricles  and  ventricles,  stimulation  of  the  vagus  enfeebles  the 
auricular  beat  and  may  also  cause  a  complete  heart-block  as  shown  in 
the  tracing  reproduced  in  Fig.  66.  It  is  important  to  point  out  here, 
however,  that  under  certain  conditions  the  vagus  may  appear  to  increase 
rather  than  decrease  the  conductivity  of  the  tissue  in  the  auriculoven- 


Fig.  66. — Tracing  to  show  that  vagus  stimulation  may  diminish  transmission  from  auricles  to 
ventricles.  It  shows  the  effect  of  stimulating  the  left  vagus  on  partial  (2/1)  block  produced  on 
heart  of  turtle  by  application  of  clamp  at  auriculoventricular  junction.  Stimulation  at  4,  depressed 
the  conductivity  and  weakened  the  auricular  contractions  (lower  tracing)  without  slowing  their 
rate.  The  result  was  an  increase  in  the  degree  of  block  with  cessation  of  ventricular  contractions 
(upper  tracing).     Initial  auricular  rate  =  35   per  minute.      (From   Carrey.) 

tricular  junction;  for  example,  it  has  been  observed  in  the  turtle  heart 
that  when  a  clamp  is  so  tight  as  to  produce  complete  block — that  is  to 
say,  to  render  the  ventricle  inactive  while  the  auricle  is  still  beating  at 
the  usual  rate — stimulation  of  the  vagus,  besides  causing  the  auricles  to 
become  distinctly  slowed,  may  at  the  same  time  cause  the  ventricles  to 
respond  to  the  auricular  beats.  This  result  is  probably  due  to  the  better 
chances  of  slow  beats  getting  through  the  junction  than  those  which  are  so 
frequent  as  to  crowd  one  another  on  the  narrow  bridge  wdiich  the  con- 
stricted tissue  offers  to  their  passage  (Fig.  67). 

Very  important  work  was  contributed  in  this  field  by  G.  R.  Mines13 
shortly  before  his  lamentable  death.  He  found  that  the  local  applica- 
tion of  atropine  to  the  sinus  eliminates  the  effect  of  stimulation  of  the 
(intracranial)  vagus  on  the  rate  of  the  heartbeat,  while  the  effect  on  the 


220 


THE    CIRCULATION    OF    THE    BLOOD 


auriculoventricular  junction  and  on  the  ventricle  remains.  After  the 
atropinization,  vagus  stimulation  delays  the  transmission  of  beat  from 
auricle  to  ventricle  and  shortens  the  time  of  each  beat  in  the  ventricle. 
It  was  further  found  that  by  the  local  application  of  atropine  various 
parts  of  theN  ventricle  can  be  rendered  irresponsive  to  the  influence  of 
the  vagus  and  the  effects  of  this  nerve  on  the  form  of  the  cardiogram 
modified  at  will.  These  results  have  an  important  bearing  in  the  in- 
terpretation of  the  cause  of  the  T-wave  of  the  electro-cardiogram 
which  will  be  referred  to  later.  Mines'  results  show  that  the  proba- 
ble explanation  is  that  the  T-A\ave  is  due  to  the  greater  duration  of  the 
excitatory  state  at  the  base  than  at  the  apex,  for  by  altering  the  relative 
duration  of  this  state  at  base  and  apex  by  the  above  methods,  he  could 
cause  the  T-wave  to  appear  or  disappear. 

The  direct  excitability  of  the  heart  muscle  to  external  stimuli  is  also 
depressed  during  vagus  stimulation.     This  effect  is,  however,  not  evi- 


Fig.  67. — Tracing  to  show  that  vagus  stimulation  may  facilitate  transmission  from  auricles  to 
ventricles.  It  shows  the  effect  of  right  vagus  stimulation  on  heart-hlock  produced  in  the  turtle  by 
a  clamp.  Upper  tracing  records  ventricle;  lower  tracing,  auricles.  Weak  faradization  of  the  right 
vagus  nerve  beginning  at  A  affected  the  degree  of  block  only  at  f  ,  when  a  lengthened  period 
between  auricular  contractions  caused  a  single  ventricular  contraction.  At  B  stronger  faradiza- 
tion of  the  same  nerve  produced  marked  slowing  of  the  auricles,  in  consequence  of  which  the  block 
disappeared  and  the  ventricles  contracted  after  each  auricular  contraction.  Block  reappeared  when 
the   rate  again  became  rapid.     Initial  auricular  rate  =  36   per   minute.      (From   Garrey.) 

dent  in  the  case  of  all  hearts,  but  is  seen  in  those  of  certain  fishes  (e.  g., 
the  eel). 

The  Mammalian  Heart. — The  action  of  the  vagus  on  the  mammalian 
heart  may  be  investigated  either  by  exposing  the  heart  and  connecting 
the  auricles  and  ventricles  with  specially  designed  recording  levers 
(myocardiograph),  or  if  we  desire  to  study  the  influence  on  the  heart  as 
a  whole,  by  taking  a  blood-pressure  tracing  from  one  of  the  large  arteries 
by  means  of  a  spring  manometer.  The  results  are  in  general  similar  to 
those  observed  on  the  frog  or  turtle  heart,  the  main  effects  being  de- 
veloped on  the  auricle.  Considerable  differences  are  found  in  the  effect 
on  the  heart  as  a  whole  in  different  animals,  particularly  with  regard  to 
the  facility  with  which  escapement  occurs.     In  the  dog  when  the  vagus 


THE   CONTROL   OF   THE   CIRCULATION  221 

is  continuously  stimulated,  the  heart  is  likely  to  remain  inhibited  for  a 
longtime,  whereas  in  the  ca1  the  inhibition  is  very  quickly  broken  into 

by  escapement.  If  the  tracing  is  taken  directly  from  the  heart,  it  will 
frequently  be  observed  in  the  dog  that,  when  the  escapement  occurs  dur- 
ing vagus  stimulation  it  is  only  the  ventricle  that  is  heating,  the  auricles 
still  remaining  inhibited. 

If  the  stimulation  of  the  vagus  is  discontinued  after  some  time  in  an 
animal  whose  blood  pressure  is  being  recorded,  the  pressure  will  not 
only  quickly  recover,  but  will  usually  overshoot  the  normal  level,  mainly 
because  of  the  asphyxia  which  has  been  produced  during  the  period  of 
inhibition.  The  asphyxia  raises  the  hydrogen-ion  concentration  of  the 
blood  and  this  stimulates  both  the  vasoconstrictor  center  and  the  heart 
action  (page  168).  The  increased  heart  action  is  also  partly  owing  to  the 
fad  that  during  vagus  inhibition  the  beating  power  of  the  heart  becomes 
improved   (page  225). 

As  an  outcome  of  recent  work,14  it  has  been  shown  that  the  right  vagus 
nerve  acts  mainly  on  the  sinoauricular  node,  and  the  left  vagus  on  the 
auriculoventricular  bundle.  This  is  in  agreement  with  the  observations 
described  above  on  the  cold-blooded  heart  (page  217).  Stimulation  of  the 
right  vagus  always  causes  slowing  and  weakening  of  both  the  auricular 
and  the  ventricular  beats,  but  stimulation  of  the  left  vagus  is  sometimes 
observed  to  have  but  little  influence  on  the  auricular  beat,  although  it 
may  produce  a  condition  of  partial  heart-block;  or,  if  a  clamp  is  ap- 
plied to  the  auriculoventricular  bundle  so  as  to  produce  a  partial  heart 
block,  then  during  stimulation  of  the  left  vagus,  the  block  may  become 
complete.  There  is,  however,  a  considerable  overlapping  of  these  in- 
fluences, at  least  in  the  case  of  the  left  vagus,  for  this  nerve  also  acts 
considerably  on  the  ventricle,  influencing  perhaps  not  so  much  the  rate 
as  the  force  of  the  contraction.  It  has  been  found  experimentally  that, 
in  order  to  demonstrate  the  specific  action  of  the  left  vagus  on  the  bun- 
dle, it  is  most  suitable  to  study  the  relationship  between  auricular  and 
ventricular  beats  when  the  auricle-  is  beating  rapidly  as  during  the 
application  of  artificial  (electrical)  stimuli  to  it.  Ordinarily  the  con- 
traction produced  by  each  stimulus  passes  into  the  ventricle,  but  during 
stimulation  of  the  left  vagus  it  is  found  that  every  contraction  does  not 
pass.  These  experiments  raise  the  question  as  to  what  the  influence  of 
either  nerve  may  be  in  blocking  impulses  from  the  auricles  to  the  ven- 
tricles when  auricular  fibrillation  is  present.  It  might  be  expected  that 
the  left  vagus  would  prove  more  effectual  in  this  regard,  but  actually  it 
has  been  found  that  both  vagi  have  the  same  effect. 

Tonic  Vagus  Action.— Impulses  are  constantly  passing  along  the  vagi 
to  the  heart,     On  account  of  this  so-called  tonic  action,  the  heart  rate 


222  THE    CIRCULATION    OF    THE    BLOOD 

increases  when  the  continuity  of  the  vagus  nerve  is  broken  either  by 
cutting  or  by  freezing  a  portion  of  nerve  (Fig.  26).  The  effect  is  usually 
inconspicuous  when  one  nerve  only  is  cut,  but  in  most  mammals  it  be- 
comes quite  marked  when  both  are  cut.  Change  in  the  heart  rate  pro- 
duced by  muscular  effort  is  much  more  gradual  in  animals  with  marked 
vagus  tone,  such  as  hunting  dogs,  than  in  those  with  little  vagus  tone,  as  in 
domestic  rabbits.  The  degree  of  vagus  tone  therefore  bears  a  relation- 
ship to  the  staying  power  of  the  animal  for  prolonged  muscular  effort. 
It  is  usually  ill  developed  in  cold-blooded  animals.  It  is  quite  marked 
in  the  case  of  man,  as  is  evident  on  observing  the  heartbeat  before  and 
after  giving  a  sufficient  dose  of  atropine  to  paralyze  the  termination  of 
the  vagus  in  the  heart. 

The  exact  location  of  the  nerve  cells  that  form  the  center  of  discharg- 
ing impulses  along  the  vagus  fibers  to  the  heart  can  not  be  made  out 
with  certainty,  but  they  are  no  doubt  part  of  the  great  motor  nucleus 
(ambiguns),  from  which  arise  the  fibers  not  only  of  the  vagus  but  of 
the  glossopharyngeal  nerve.  The  tone  of  this  vagus  center  is  almost 
without  doubt  dependent  upon  the  constant  transmission  to  it  along  the 
sensory  or  afferent  fibers  of  impulses  coming  from  various  portions  of 
the  body.  According  to  the  strength  or  number  of  these  impulses,  the 
tone  may  be  increased  or  diminished,  thus  altering  the  rate  of  the  heart. 
It  is  possible  of  course  that  the  tone  can  be  maintained,  independently 
of  the  afferent  impulses,  by  the  action  on  the  center  of  chemical- meta- 
bolic products  or  hormones  produced  in  the  cells  or  carried  to  them  in 
the  blood.  AVe  know  at  least  that,  like  the  respiratory  center,  that  of 
the  vagus  is  excitable  by  such  hormones  as  the  hydrogen-ion  concen- 
tration of  the  blood.  The  tonicity  of  the  vagus  center  is.  however,  mainly 
dependent  upon  the  passage  to  it  of  afferent  impulses,  and  as  evidence 
for  this  conclusion  may  be  cited  the  observation  that,  after  section  of 
most  of  the  afferent  nerves  to  the  medulla  (as  by  cutting  the  spinal  cord 
high  up  in  the  cervical  region),  subsequent  section  of  the  two  vagi  does 
not  produce  anything  like  the  usual  degree  of  change  in  the  heart  rate. 

The  Afferent  Vagus  Impulses. — The  afferent  vagus  impulses  may  come 
from  practically  any  part  of  the  body,  having  been  first  discovered  by 
the  simple  experiment  of  tapping  the  abdomen  of  the  frog  with  the  han- 
dle of  a  scalpel,  when  slowing  of  the  heart  rate  is  observed.  Cutting  the 
vagi  abolishes  the  reflex.  Similar  cardiac  inhibition  is  produced  by  me- 
chanical stimulation  of  the  tail  or  gills  of  an  eel.  In  mammals  stimula- 
tion of  the  central  end  of  any  sensory  nerve  usually  slows  the  heart, 
though  sometimes  the  opposite  effect  occurs.  The  pulmonary  branches 
of  the  vagus  are  particularly  sensitive  in  producing  reflex  inhibition, 
and  distinct  results  are  usually  obtained:  by  stimulation  of  the  termina- 


THE   CONTROL  OF   THE   CIRCULATION  223 

t ions  of  the  fifth  nerve  in  the  mucosa  of  the  upper  respiratory  passages, 
as  by  inhaling  ammonia  vapor;  by  stimulation  of  the  sensory  nerve  end- 
ings in  the  pharynx,  as  by  swallowing;  and  of  the  mucosa  of  the  larynx, 
as  when  a  substance  is  "swallowed  the  wrong  way."  The  sensory 
nerves  of  the  abdominal  viscera  seem  to  be  particularly  active  on  the 
vagus  center,  as  is  seen  in  irritation  of  the  sensory  nerves  of  the  stom- 
ach such  as  occurs  in  gastritis.  Profound  inhibition  may  also  be  caused 
by  violent  stimulation  of  the  mesentery,  as  from  a  blow  on  the  abdo- 
men, or  by  irritation  of  the  sensory  nerves  of  the  intestine,  either  me- 
chanical or  because  of  disease.  Another  interesting  illustration  of  affer- 
ent vagus  stimulation  is  obtained  by  pressure  on  the  outer  canthus  of 
the  eye.  This  oculomotor  vagus  reflex,  as  it  is  called,  is  very  marked 
in  some  individuals. 

Through  which  of  these  afferent  paths  it  may  be  that  the  constant 
stimuli  are  transmitted  to  the  vagus  center  to  enable  it  to  maintain  its 
tone,  can  not  be  said,  although  it  is  very  likely  to  be  through  the  vis- 
ceral nerves. 

In  considering  the  cause  for  an  observed  change  in  heart  rate,  we 
must  of  course  bear  in  mind  the  possibility  that  the  action  may  have 
occurred,  not  through  the  vagus  center,  but  through  the  sympathetic 
center.  Thus,  when  the  heart  becomes  quicker,  it  may  be  OAving  either 
to  diminution  in  the  vagus  tone  or  to  an  increase  in  the  discharges 
along  the  sympathetic  nerve  from  the  augmentor  center.  That  such 
reflex  action  through  the  augmentor  center  does  occur  under  experi- 
mental conditions  has  been  clearly  shown;  for  example,  if  both  vagus 
nerves  are  cut  and  the  peripheral  end  of  one  of  them  stimulated  mod- 
erately, so  as  to  hold  the  heart  at  about  its  normal  rate,  the  stimulation 
of  certain  sensory  nerves  may  cause  increase  in  the  heart  rate.  Reflex 
sympathetic  control  of  the  heartbeat  is  howrever  no  doubt  much  less 
important  than  control  through  the  vagus  center.  When  it  does  exist 
it  means  that  the  actual  rate  of  the  heartbeat  at  any  given  moment 
must  represent  the  algebraic  sum  of  two  opposing  influences,  with  that 
of  the  vagus  preponderating.  The  advantage  of  such  a  double  inner- 
vation is  that  it  insures  prompter  adjustment  of  the  beat.  If,  for  ex- 
ample, for  any  reason  quickening  of  the  heart  rate  is  necessary,  it  is 
brought  about  most  promptly  if  the  vagus  tone  is  diminished  at  the  same 
moment  that  the  sympathetic  tone  is  increased.  Such  reciprocal  action 
of  antagonistic  influences  is  the  usual  rule  in  the  animal  economy.  Thus, 
when  the  knee  joint  flexes,  it  does  so  not  merely  because  stimulating 
impulses  are  transmitted  to  the  hamstring  muscles,  but  also  because  at 
the  same  moment  inhibiting  impulses  are  transmitted  to  the  extensor 
muscles  (see  page  814). 


224  THE    CIRCULATION    OF    THE    BLOOD 

Several  possibilities  have  to  be  kept  in  mind  when  Ave  attempt  to 
determine  the  exciting  cruise  for  an  observed  change  in  the  heart  rate  in 
man.  Tims,  a  slowing  of  the  rate  may  be  due  to  meehanical  stimulation 
of  the  vagus  trunk,  as  in  pressure  on  the  nerves  by  a  tumor  or  aneurism 
in  the  neck.  That  such  mechanical  irritation  may  stimulate  the  vagus 
is  easily  demonstrated  in  many  individuals  by  applying  pressure  to  the 
vagus  where  it  lies  in  the  neck  in  front  of  the  sixth  cervical  vertebra. 
Such  pressure  sometimes  produces  so  profound  an  inhibition  of  the  heart 
that  temporary  loss  of  consciousness  occurs.  It  is  often  an  unsafe  ex- 
periment to  perform. 

Change  in  the  heart  rate  in  man  may  be  caused  by  direct  stimulation 
of  the  vagus  center,  as  by  the  presence  of  a  tumor  or  a  blood  clot  in  the 
medulla,  or  by  the  action  on  the  center  of  some  unusual  hormone  in  the 
blood.  A  general  increase  in  intracranial  pressure  also  stimulates  the 
vagus  center.  The  slowing  of  the  heart  which  occurs  in  asphyxia  might 
be  due  either  to  the  action  of  hormones  (hydrogen-ion  concentration) 
in  the  blood  as  the  result  of  the  asphyxia,  or  to  the  increased  intra- 
cranial pressure.  That  the  latter  is  the  more  important  cause  is  shown 
by  the  fact  that,  if  the  rise  in  blood  pressure  is  prevented  by  connecting 
an  artery  with  a  mercury  valve, — that  is,  with  a  tube  dipping  into  a 
cylinder  of  mercury  to  a  depth  corresponding  to  the  normal  blood 
pressure,  so  that  when  the  pressure  tends  to  rise  the  blood  escapes, — 
the  slowing  of  the  heart  is  not  observed.  The  excitability  of  the  afferent 
vagus  fibers  in  the  lungs  is  greatly  increased  during  the  earlier  stage 
of  chloroform  administration. 

Finally  it  should  be  pointed  out  that,  although  Ave  have  no  voluntary 
control  of  the  activity  of  the  vagus  center,  its  activities  are  subject 
to  great  variation  as  a  result  of  impulses  transmitted  from  centers  higher 
up  in  the  cerebrospinal  axis.  It  is  by  the  operation  on  the  vagus  center  of 
such  impulses  that  changes  in  heart  rate  occur  during  emotional  ex- 
citement, fright,  etc.  The  increased  heart  rate  in  muscular  exercise  is 
probably  dependent  upon  a  number  of  causes,  such  as  the  irradiation  of 
the  motor  impulses  on  to  the  cardiac  centers  (see  page  412),  the  rise  in 
temperature  and  changes  in  the  hydrogen-ion  concentration  of  the  blood, 
etc. 

Mechanism  of  Action  of  Vagus  on  the  Heart. — Physiologists  have  nat- 
urally been  curious  as  to  the  exact  manner  in  which  the  vagus  nerve 
brings  about  inhibition  of  heart  action.  Similar  inhibition  as  a  result 
of  stimulation  of  efferent  nerves  exists  in  the  case  of  the  dilator  fibers 
to  the  blood  vessels  (page  234)  and  the  sympathetic  nerve  to  the  intes- 
tine (page  467).  Inhibition  of  voluntary  muscles  can  be  produced  only 
through  the  central  nervous  svstem  by  stimulation  of  afferent  nerves 


Left  Ant.  Caval  vein 


.Riqht  Ant  Caval  vein 


Preganglionic  rreurOn 

•  Postganglionic  neuron 


Inf  Vena  cava 


Hook  from 
'Heart  lever 


Bidders    Ganglion 
in  auriculo-ventricular  junction 


stimulating  electrodes 

in  $mo -auricular  junction  [Crescent] 

Sympathetic  fibres--  dotted  lines 

Fig.    68.  —  Diagram    to    show    the    innervation    cf    the    heart    in    the    frog    or    turtle.      The    electrodes 
are   represented  as  applied  to  the  white  crescentic  line  where  they  will   stimulate  some  postganglionic 

libers.       (  From    Jackson.) 


THE    CONTROL   OF    THE    CIRCULATION  225 

(page  814).    It  is  not  the  nerve  fibers  themselves  that  are  responsible 

for  the  inhibitory  effect,  for  it  has  been  found  that  if  the  peripheral 
end  of  a  cut  vagus  nerve  is  connected  with  the  central  end  of  one  of 
the  anterior  roots  of  the  cervical  portion  of  the  spinal  cord,  the  axons 
of  the  latter  when  they  grow  down  into  the  vagus  trunk  during  the 
regeneration  which  follows,  stimulation  of  the  regenerated  fibers  will 
still  produce  inhibition  of  the  heart.  The  nature  of  the  fibers  can  not 
therefore  be  the  factor  upon  which  the  inhibiting  influence  of  the  vagus 
is  dependent.  This  leaves  the  terminal  apparatus  of  the  vagus  fibers  in 
the  heart  as  the  structures  in  which  the  stimulus  conveyed  to  them  is 
rendered  inhibitory  in  nature. 

There  has  been  considerable  speculation  as  to  what  kind  of  change 
must  be  occurring  in  the  heart  in  order  to  cause  the  inhibition,  but 
practically  nothing  that  is  definite  is  known.  One  significant  fact,  how- 
ever, is  that  the  electrical  current  led  off  through  nonpolarizable  elec- 
trodes from  two  portions  of  the  auricle  one  of  which  is  injured,  does  not 
take  the  same  direction  when  the  vagus  nerve  is  stimulated  as  that  which 
it  takes  when  the  motor  nerve  of  a  similarly  observed  muscle  is  stimu- 
lated. A  positive  instead  of  a  negative  variation  is  observed.  Now, 
since  a  negative  variation  is  always  accompanied  by  active  chemical 
breakdown  changes  occurring  in  the  muscle  to  supply  its  energy  of 
contraction,  it  is  assumed  that  the  positive  variation  accompanying  stim- 
ulation of  the  vagus  must  indicate  that,  instead  of  a  katabolic  process, 
a  building  up,  or  anabolic  process,  is  being  excited.  This  conclusion 
would  fit  in  perfectly  with  the  well-known  fact  that,  after  the  heart  has 
been  held  in  standstill  for  some  time  by  vagus  stimulation,  the  beats  are 
stronger  after  the  inhibition  has  passed  off  than  they  were  before.  The 
vagus  seems  to  have  a  conserving  influence  on  the  heart.  During  the 
inhibition  produced  by  it  energy  material  is  apparently  stored  up  in  the 
heart,  so  that  when  the  beat  is  reestablished  it  is  stronger  than  before. 

The  Manner  of  Termination  of  the  Vagus  Fibers  in  the  Heart. — This 
subject  is  of  considerable  pharmacologic  and  therefore  therapeutic  in- 
terest. In  approaching  the  problem  it  must  be  remembered  that  the 
vagus  fibers  belong  to  the  so-called  cerebral  autonomic  system  of  nerves 
(see  page  882).  They  are  therefore  fibers  which  have  cell  stations  situ- 
ated near  their  peripheral  termination — cell  stations,  that  is  to  say,  in 
which  ganglionic  medullated  fibers,  by  forming  synapses  around  nerve 
cells,  become  connected  with  postganglionic  nonmedullated  fibers.  The 
existence  of  ganglia  in  the  heart,  particularly  of  the  frog,  has  been 
known  for  a  long  time.  These  ganglia  are  located  at  the  sinoauricular 
junction,  at  the  interauricular  septum,  and  in  the  ventricle  near  the 


226 


THE    CIRCULATION    OP    THE    BLOOD 


auriculoventricular  junction.    The  function  of  the  ganglia  is  to  serve  as 
cell  stations  on  the  course  of  the  vagus  nerves.     (Fig.  68.) 

Nicotine  is  a  drug  which  in  certain  concentrations,  if  applied  locally 
to  sympathetic  ganglia,  specifically  paralyzes  the  synapses  between  the 
ends  of  the  preganglionic  fibers  and  the  cells  from  which  the  post- 
ganglionic fibers  arise.  If  this  drug  is  applied  in  a  1  per  cent  solution 
to  the  heart,  stimulation  of  the  vagus  trunk  no  longer  produces  inhibi- 
tion, but  if  the  stimulus  is  applied  to  a  portion  of  the  heart  known  as 


■V       /V/V       /Y       /V/V/V       /V       /V   •  /V      /V      /V       /VA./N./V/V 


Xa^oM^otf-K^tU^  StuttrruU. 


Fig.  69. — Frog  heart  tracing  showing  the  action  of  nicotine.  The  vagus  trunk  was  stimulated 
as  indicated.  In  the  normal  (lower)  tracing  inhibition  occurs  hut  after  nicotine  (second  tracing) 
no  inhibition  follows.  Stimulation  of  the  crescent  in  the  next  two  lines  still  is  followed  by  inhibi- 
tion.    The   final   effects   of   the   drug  are   shown   in  the   last   two    (upper)    tracings.      (From  Jackson.) 

the  white  crescentic  line,  inhibition  still  occurs,  because  at  this  point  the 
postganglionic  nerve  fibers  come  near  to  the  surface  and  therefore  are 
stimulated  (Fig.  69).  On  the  other  hand,  atropine  is  a  drug  which 
paralyzes  the  postganglionic  fibers,  so  that  after  its  application  to  the 
heart  inhibition  can  not  be 'produced  by  stimulating  either  the  vagus 
trunk  or  the  white  crescentic  line.  Pilocarpine  and  muscarine  are  drugs 
which  have  -an  action  exactly  opposite  or  antagonistic  to  that  of  atro- 


Medulla 

oblongata 

rv.x/ 

Cervical  1 


Accessory  n. 
fo  trapezius 


Spinal 
medulla 
{cord) 


Rami 

communican- 
tes  going  to 
Symp.  gang, 
(preganglionic) 
Ansa 

subclavia 
(Annulus  of 
Vieussensh* 

Thoracic -3 
nerves 


Electrodes 
(Acceleration,  or 


N.I 

Postganglionic  fibers 

are  dotted  thus 


Jugular  ganglion  (Gang,  of  the  root) 
Depressor  (Fall  in  pressure  or  slowing  of  heart.) 
(Sensory)    Separate  nerve  in  rabbit  and  opossum. 

Nodosum  ganglion  (Gang,  of  the  trunk)      ^"r/ngton) 
^■Inhibitory  cranial  autonomic  fibers 

Superior  cervical  ganglion 
Descending  sympathetic  fibers  in  cord 
^Cervical  vago- sympathetic  trunk 


^Electrodes    (slowing  or  stoppage  of 
Subclavian       heart.  Augmentation  in  some 

animals.) 
Aortic  drch 


First  thoracic  ganglion 
(Stellate) 


augmentation  of  heart.) 


Fig.  70.  -Schematic  representation  of  the  innervation  of  the  heart  of  the  mammal.  The  red 
continuous  lines  represent  the  sympathetic  (accelerator)  preganglionic  fibers,  and  the  broken  red 
lines,  their  postganglionic  fibers.  The  cell  stations  are  in  the  inferior  cervical  and  stellate  ganglia, 
some'  extending  up  to  the  superior  ceivical  ganglion.  The  green  continuous  lines  represent  the 
vagus  preganglionic  libers,  and  the  broken  green  lines,  their  postganglionic  fibers.  The  cell  stations 
in  this  case  are  located  in  the  heart  itself.  It  will  be  observed  that  electrodes  applied  to  the  so- 
called   vagus   low   down   in   the   neck   ma>    stimulate   some   sympathetic   fibers.      (From  Jackson.) 


THE   CONTBOTj   OF   THE   CIRCULATION  227 

pine;  that  is,  they  stimulate  the  postganglionic  fibers  and   produce  a 
slowing  and  possibly  an  enfeebling  of  the  beat. 

In  the  mammalian  hearl  a  large  number  of  1  lie  filters  in  the  right 
vagus  nerve  proceed  directly  to  the  sinoauricular  node,  where  it  can 
be  shown  histologically  that  considerable  masses  of  nervous  tissue  exist. 
On  the  other  hand,  the  great  majority  of  the  fibers  in  the  left  vagus 
proceed  to  the  auriculoventricular  bundle,  in  which  also  nervous  struc- 
tures are  abundant  (page  184).  As  already  indicated,  the  experimental 
results  which  follow  stimulation  of  either  nerve  can  be  explained  by  the 
influence  which  the  nerve  exerts  on  the  particular  structure  to  which 
the  majority  of  its  fibers  proceed.  In  brief,  stimulation  of  the  right 
vagus  is  likely  to  produce  slowing  and  weakening  of  the  beat,  whereas 
stimulation  of  the  left  vagus  is  more  likely  to  institute  a  condition  of 
partial  heart-block. 

On  account  of  the  different  results  which  may  be  obtained  by  stimu- 
lating the  vagus,  some  authorities  have  assumed  that  the  heart  must 
contain  four  kinds  of  fiber,  more  strictly,  of  vagus  nerve  endings,  one  for 
each  kind  of  influence  which  the  vagus  can  develop.  These  four  influ- 
ences are,  it  will  be  remembered,  on  the  strength,  the  rate  and  the 
propagation  of  the  heartbeat,  and  the  excitability  of  the  cardiac  muscle. 
It  is,  however,  almost  certainly  unnecessary  to  make  such  an  assump- 
tion, for  the  results  can  be  explained  as  merely  dependent  upon  dif- 
ferent degrees  of  stimulation  of  the  same  kind  of  fiber  and  upon  the 
exact  part  of  the  heart  to  which  the  fiber  runs.  Sometimes,  for  ex- 
ample, when  the  right  vagus  nerve  is  stimulated  very  feebly,  there  may 
be  only  a  diminution  in  the  force  of  the  beats  without  any  change  in 
their  rate,  indicating  that  the  effect  has  been  upon  the  musculature  of 
the  auricular  walls  and  not  on  the  sinoauricular  node.  If  the  stimulus 
is  increased  a  little,  then  both  an  enfeebling  and  a  slowing  of  beat  occur, 
indicating  that  the  stimulus  has  now  passed  both  to  the  auricular  mus- 
culature directly  and  to  the  sinoauricular  node. 

The  Sympathetic  Control 

The  effect  of  the  sympathetic  nerve  on  the  heart  may  be  described  as 
being  exactly  opposite  to  that  of  the  vagus.  The  pathway  along  which 
the  fibers  of  this  nerve  travel  to  the  heart  is  more  or  less  a  devious  one. 
They  arise  in  the  mammal  from  nerve  cells  in  the  gray  matter  in  the 
upper  thoracic  portion  of  the  spinal  cord.  The  fibers  leave  by  the  cor- 
responding spinal  roots  and  pass  by  the  white  rami  communicantes  into 
the  sympathetic  chain,  up  which  they  travel  to  the  stellate  and  inferior 
cervical  ganglia.  Around  the  nerve  cells  of  the  stellate  ganglion  the 
fibers  end  by  synapsis,  and  the  axons  of  the  cells  are  then  continued  on 


228 


THE    CIRCULATION   OF    THE   BLOOD 


as  postganglionic  fibers,  proceeding  to  the  heart  through  branches  com- 
ing off  from  the  stellate  ganglion  itself,  or  from  the  ansa  subclavii  or 
inferior  cervical  ganglion.  (Fig.  70).  In  cold-blooded  animals,  such  as 
the  frog,  the  sympathetic  fibers  run  up  to  the  upper  end  of  the  cervical 
sympathetic  and  join  the  vagus  immediately  after  it  leaves  the  cranial 
cavity.  They  then  proceed  along  with  this  nerve — forming  the  vago- 
sympathetic— to  the  heart.  The  effect  of  stimulation  is  shown  in  Fig.  71. 
The  sympathetic  nerve  differs  from  the  vagus  in  that  a  much  longer  la- 
tent period  elapses  before  its  influence  becomes  effective,  and  this  persists 
for  a  much  longer  period  after  the  stimulus  is  withdrawn.    If  the  vagus 


B. 

Fig.    71. — Tracings   showing   the   effects   on    the   heartbeat   of    the   frog   resulting   from    stimulation    of 
the    sympathetic    nerves    prior    to    their    union    with    the    vagus    nerve.      (From    Brodie.) 

and  sympathetic  are  stimulated  at  the  same  time,  as  by  exciting  the  vago- 
sympathetic in  the  frog,  the  first  effect  observed  is  that  of  the  vagus 
usually  followed,  after  removal  of  the  stimulus,  by  the  sympathetic  ef- 
fect. If  the  stimulus  is  maintained  for  a  long  time,  so  that  the  vagus 
becomes  fatigued,  escapement  will  occur  earlier  than  with  pure  vagus 
stimulation,  and  augmentation  may  become  apparent.  The  sympathetic 
influence  is,  however,  never  so  strong  as  that  of  the  vagus.  The  two 
nerves  are  therefore  not  antagonistic  in  the  sense  that  the  one  neutralizes 
the  effect  of  the  other;  but  when  both  are  stimulated,  the  heart  responds 
first  to  the  vagus  and  later  to  the  sympathetic. 


CHAPTER  XXVI 
THE  CONTROL  OF  THE  CIRCULATION  (Cont'd) 

THE  NERVE  CONTROL  OF  THE  PERIPHERAL  RESISTANCE 

As  already  explained,  the  nerve  control  of  the  peripheral  resistance 
takes  place  through  the  action  of  vasoconstrictor  and  vasodilator  nerve 
fibers  on  the  musculature  of  the  arteriole  walls.  The  vasoconstrictor 
impulses  like  those  in  the  vagus  of  the  heart  are  tonic,  so  that  when  a 
nerve  containing  such  fibers  is  cut,  the  corresponding  blood  vessels  un- 
dergo dilatation  (see  page  135),  and  when  their  peripheral  ends  are  stim- 
ulated artificially,  constriction  occurs.  On  the  other  hand,  the  vasodi- 
lator impulses  do  not  appear,  at  least  under  ordinary  circumstances,  to 
be  tonic,  so  that  the  cutting  of  such  fibers  does  not  cause  vasoconstriction ; 
their  stimulation,  however,  causes  marked  dilatation.  Vasomotor  fibers 
are  contained  in  most  of  the  efferent  (motor)  nerve  trunks,  and  to 
detect  their  presence  the  nerve  must  be  either  cut  or  stimulated  and  the 
condition  of  the  blood  vessels  of  the  innervated  area  observed. 

Methods  for  the  Detection  of  Constriction  or  Dilatation 

Several  methods,  varying  with  the  exact  area  under  observation,  can 
be  used  for  the  detection  of  vasoconstriction  or  dilatation.  In  many  cases 
visual  inspection  is  sufficient,  as  in  the  well-known  experiment  of  Claude 
Bernard  on  the  blood  vessels  in  the  ear  of  the  rabbit  (see  Fig.  106).  When 
this  is  held  with  a  light  behind  it,  and  the  cervical  sympathetic  of  the 
corresponding  side  is  cut,  marked  dilatation  will  become  evident  and 
vessels  will  spring  into  view  where  previously  there  were  none  visible. 
Visual  inspection  is  usually  also  a  satisfactory  method  of  demonstrat- 
ing vasodilatation  or  constriction  in  exposed  glands,  in  mucous  pas- 
sages and  in  the  vessels  of  the  skin. 

Another  comparatively  simple  method  is  the  observation  of  the  tem- 
perature of  the  part,  this  being  particularly  useful  when  the  vascular 
area  is  one  situated  in  the  peripheral  part  of  the  body,  such  as  the  hand 
or  foot  (see  page  200).  When  dilatation  occurs  the  temperature  of  the 
part  rises,  because  the  warmer  blood  from  the  viscera  flows  with  greater 
freedom  through  the  peripheral  regions,  where  it  is  cooled  off  by  radia- 
tion.   When  a  thermometer  is  placed  between  the  toes  of  a  dog  or  cat,  a 

229 


230 


THE    CIRCULATION    OF    THE    BLOOD 


distinct  rise  in  temperature  a\  ill  be  observed  when  the  sciatic  nerve  of  the 
corresponding  limb  is  cut.  The  application  of  this  principle  in  deter- 
mining the  mass  movement  of  blood  by  the  amount  of  heat  given  off  from 
the  hands  or  feet  has  already  been  explained. 

Other  methods  depend  upon  observation  of  the  outflow  of  blood  from 
the  veins  of  the  part.  A  simple  application  of  this  method  can  be  used  in 
the  case  of  the  ear  of  the  rabbit.  If  the  tip  of  the  ear  is  cut  off,  bleeding 
under  ordinary  circumstances  is  only  very  slight,  but  if  the  cervical 
sympathetic  is  cut,  it  becomes  quite  marked,  slowing  down  again  or 
even  stopping  entirely  when  the  peripheral  end  of  the  nerve  is  stimu- 
lated. By  making  measurements  of  the  volume  of  the  outflow  of  blood 
from  a  vein  by  this  method,  the  extent  of  constriction  or  dilatation  can 


tube  to  recorder 


enclosed 
membrane 


Fig.   72. — Roy's  kidney  oncometer.      (From  Jackson.) 


be  followed  quantitatively.  Vasodilatation  also  causes  changes  in  the 
character  of  the  venous  flow,  the  usually  continuous  flow  becoming'  pul- 
satile and  the  color  of  the  blood  brightening.  Comparison  of  the  pressures 
in  the  arteries  and  the  veins  of  a  part  is  also  often  of  value  in  the  detec- 
tion of  changes  in  the  caliber  of  the  blood  vessels,  for,  of  course,  the 
greater  the  difference  in  pressure  between  the  two  manometers,  the 
greater  must  be  the  resistance  offered  to  the  flow. 

For  experimental  purposes,  however,  the  standard  method  is  that 
known  as  the  plethysmography.  For  this  purpose  the  organ  or  tissue  is 
enclosed  in  a  so-called  plethysinograph  or  volume  recorder,  the  prin- 
ciple of  which  will  be  clearly  seen  by  consultation  of  the  accompanying 
diagram  of  one  adapted  for  the  kidney  (Fig.  72).  Any  increase  de- 
tected by  this  means  in  the  volume  of  the  part  must  be  due  either  to 


THE   CONTROL   OF   THE   CIRCULATION  231 

an  increase  in  blood  flowing  into  the  vessels  because  of  increased  heart 
action  or  to  a  local  vasodilatation;  and  vice  versa,  when  shrinkage  oc- 
curs. We  can  no1  tell  from  the  volume  tracing  itself  which  of  these 
changes  is  really  responsible  for  the  observed  alteration,  but  we  can  do 
so  by  simultaneously  observing  the  mean  arterial  blood  pressure.  If  this 
falls  when  the  volume  decreases,  it  means  that  the  volume  of  blood  flow- 
ing to  the  part  must  have  become  diminished.  If,  on  the  other  hand,  the 
blood  pressure  remains  constant  or  rises  while  the  volume  decreases,  it 
means  that  the  blood  vessels  have  locally  constricted. 

Methods  for  the  Detection  of  Vasomotor  Fibers  in  Nerve  Trunks 

If  we  wish  to  find  out  through  which  nerve  trunks  a  given  vascular 
area  is  supplied  with  vasoconstrictor  or  vasodilator  impulses,  we  should 
proceed  by  the  use  of  one  of  the  above  described  methods  to  observe  the 
effect  produced  on  the  vessels  by  cutting  the  nerve  and  then  by  stimu- 
lating the  peripheral  end  of  the  cut  nerve.  As  a  result  of  such  observa- 
tions it  has  been  found  that  the  vasomotor  fibers  are  frequently  dis- 
tributed so  that  those  having  a  vasoconstricting  action  are  collected 
mainly  in  one  nerve  trunk  and  those  having  a  dilating  action  in  another; 
in  some  nerve  trunks,  however,  the  relative  numbers  of  the  opposing 
fibers  are  about  equal.  Nerves  containing  a  great  preponderance  of  vaso- 
constrictor fibers  are  the  great  splanchnic  and  the  cervical  sympathetic ; 
and  those  containing  a  great  preponderance  of  vasodilator  are  the  chorda 
tympani  nerve  to  the  submaxillary  gland  and  the  nervi  erigentes  to  the 
external  genitalia. 

It  must  be  clearly  understood  that,  although  one  kind  of  vasomotor 
fiber  may  preponderate  in  one  of  these  nerves,  yet  the  opposite  kind  is 
also  present.  In  the  cervical  sympathetic,  for  example,  some  vasodila- 
tor fibers  extending  to  the  blood  vessels  of  the  mucous  membrane  of  the 
nose  and  cheeks  can  readily  be  demonstrated,  as  shown  by  the  flushing 
of  these  parts  when  the  peripheral  end  of  the  nerve  is  stimulated;  and 
similarly,  even  in  the  great  splanchnic  nerve  itself,  vasodilator  fibers 
supplying  the  suprarenal  capsule  can  quite  readily  be  made  out.  When 
the  vasoconstrictor  fibers  greatly  preponderate  over  the  vasodilator,  the 
effect  of  the  latter  may  be  demonstrated  by  taking  advantage  of  the  fact 
that  ergot oxine  paralyzes  the  vasoconstrictor  but  not  the  vasodilator 
fibers,  so  that  after  its  administration  stimulation  of  the  great  splanch- 
nic nerve  gives  rise  to  a  vasodilatation  instead  of  a  vasoconstriction. 
The  presence  of  vasoconstrictor  fibers  in  the  so-called  vasodilator  nerves 
(chorda  tympani  and  nervi  erigentes)  has  not  however,  been  demon- 
strated. 

A  good  example  of  a  nerve  trunk  containing  about  an  equal  admix- 


232  THE    CIRCULATION    OF    THE   BLOOD 

ture  of  both  kinds  of  vasomotor  fibers  is  the  sciatic.  If  the  hind  limb  of 
a  dog  is  placed  in  a  plethysmograph  and  simultaneously  a  record  of  the 
mean  arterial  blood  pressure  taken,  it  will  be  found  on  cutting  the  sciatic 
nerve  that  the  volume  of  the  limb  increases,  whereas  the  blood  pressure 
remains  practically  constant.  Before  placing  the  limb  in  the  plethysmo- 
graph, the  muscles  must  of  course  be  paralyzed  by  means  of  curare; 
otherwise  muscular  contractions  would  confuse  the  result.  If  the 
peripheral  end  of  the  cut  nerve  is  now  stimulated,  vasoconstriction  will 
readily  be  observed.  So  far,  then,  the  results  demonstrate  the  presence 
of  vasoconstrictor  nerve  fibers  alone. 

To  demonstrate  the  presence  of  vasodilators  a  different  procedure  is 
necessary.  This  is  based  on  the  following  facts:  (1)  The  vasodilator 
nerve  fibers  degenerate  more  slowly  than  the  vasoconstrictor;  (2)  they 
are  less  depressed  in  their  excitability  by  cooling  the  nerve;  and  (3)  they 
are  more  sensitive  to  weak  slow  faradic  stimulation  than  the  vasocon- 
strictor fibers.  Accordingly,  if  we  cut  the  sciatic  nerve  two  or  three 
days  before  the  actual  experiment,  and  then,  while  observing  the  volume 
of  the  limb,  proceed  to  stimulate  the  half-degenerated  nerve  with  feeble 
electric  stimuli  of  slow  frequency  we  shall  usually  observe  a  dilatation 
of  the  limb  instead  of  constriction;  and  even  if  we  cool  a  stretch  of  a 
freshly  cut  nerve  before  applying  the  stimulus,  the  same  result  will 
often  be  obtained. 

The  Origin  of  Vasomotor  Nerve  Fibers 

Having  seen  how  the  presence  of  vasomotor  fibers  may  be  detected  in 
peripheral  nerves,  we  must  now  proceed  to  trace  them  back  to  their 
origin  from  the  central  nervous  system.  The  method  for  doing  this  con- 
sists, in  general,  in  observing  the  effect  on  the  blood  vessels  produced  by 
cutting  or  stimulating  the  various  nerve  roots  through  which  the  fibers 
might  pass  on  their  way  to  the  nerve  trunks.  As  a  result  of  such  obser- 
vations it  has  been  found  that  all  of  the  vasoconstrictor  fibers  emanate 
from  the  spinal  cord  in  the  region  between  the  level  of  the  second  thoracic 
and  that  of  the  second  or  third  lumbar  spinal  roots,  but  from  nowhere 
else  in  the  cerebrospinal  axis.  Section  of  the  spinal  cord  below  the  level 
of  the  second  lumbar  spinal  roots  produces  no  change  in  the  volume  of 
the  hind  limb,  provided  the  muscles  be  thoroughly  curarized,  nor  does 
stimulation  of  the  lower  end  of  the  cut  spinal  cord  have  any  effect.  If 
the  last  two  thoracic  or  the  first  two  lumbar  spinal  roots  are  stimulated, 
however,  evidence  of  vasoconstriction  will  be  obtained. 

The  restriction  of  the  origin  of  vasoconstrictor  fibers  to  the  above- 
mentioned  regions  of  the  spinal  cord  indicates  that  in  proceeding  to 
the  mixed  nerve  trunks  they  must  travel  along  special  nerve  paths. 


THE   CONTROL   OF   THE   CIRCULATION  -'■'>'■'> 

These  are  provided  by  the  sympathetic  chain  ;in<l  its  branches  (Kin.  'J'Jk.i. 
The  vasoconstrictor  fibers  in  the  anterior  spinal  roots  leave  the  latter 
by  way  of  the  corresponding  white  rami  communicantes,  and  pass  into 

the  neighboring  sympathetic  chain,  along  which  they  either  ascend  or 
descend,  according  to  their  ultimate  destination.  In  their  course  they 
come  into  contact  with  the  sympathetic  ganglia,  through  one  or  two  of 
which  they  may  pass  without  any  change,  but  ultimately  each  fiber  ar- 
rives at  some  ganglion,  in  which  it  terminates  by  forming  a  synapsis 
around  one  of  the  ganglionic  nerve  cells.  The  axon  of  this  nerve  cell 
then  continues  the  course  by  the  nearest  gray  ramus  eommunicans  back 
to  the  spinal  nerve  beyond  the  union  of  its  anterior  and  posterior  roots. 
Up  to  the  point  where  the  fiber  forms  a  synapsis  with  a  ganglionic  nerve 
cell,  it  is  medullated  and  is  known  as  the  preganglionic  fiber.  Beyond 
the  nerve  cell,  it  is  nonmedullated  and  is  known  as  postganglionic 
(page  877). 

The  exact  ganglion  in  which  a  given  vasoconstrictor  fiber  becomes  connected  with  a 
nerve  eel]  can  be  determined  by  the  nicotine  method  of  Langley.  Local  application  to 
the  ganglion  of  a  weak  solution  of  this  drug  (1  per  cent)  paralyzes  the  synaptic  con- 
nection, so  that  a  stimulus  applied  to  the  preganglionic  fiber  no  longer  produces  its 
effect.  Suppose,  for  example,  that  a  vasoconstrictor  fiber  has  been  found  by  the  stimula- 
tion method  to  travel  through  several  ganglia,  and  we  wish  to  determine  in  which  of 
these  the  synapsis  occurs:  we  can  do  so  by  applying  the  stimulus  at  a  point  central  to 
the  ganglia  after  painting  each  of  them  in  turn  with  the  nicotine  solution.  If  the 
application  of  the  drug  to  a  given  ganglion  is  found  to  cause  no  alteration  in  the 
effect  produced  by  stimulation,  then  we  know  that  there  can  not  be  any  synaptic 
connection  in  that  ganglion,  and  we  proceed  in  the  same  way  till  we  have  located 
the  ganglion  in  which  synapsis  occurs.  It  is  important  to  remember  that  the  post- 
ganglionic vasoconstrictor  fibers  in  a  gray  ramus  eommunicans  do  not  come  from  the 
preganglionic  fibers  of  the  corresponding  spinal  rcot,  but  from  fibers  coming  through 
white  rami  at  a  higher  or  a  lower  level. 

The  above  description  applies  to  the  vasoconstrictor  fibers  proceeding  to  the  vessels  of 
the  anterior  and  posterior  extremities,  those  for  the  former  arising  (in  the  dog)  from 
about  the  fourth  thoracic  to  the  tenth;  and  those  for  the  latter,  from  the  lowest  thoracic 
and  the  first  three  lumbar  nerve  roots.  The  cell  station  for  the  fibers  to  the  fore  limbs 
is  in  the  stellate  ganglion,  and  for  the  hind  limbs  in  the  last  two  lumbar  and  first  two 
sacral  ganglia  of  the  abdominal  sympathetic  chain. 

The  vasoconstrictor  fibers  to  the  vessels  of  the  head  and  neck  run  a  somewhat  dif- 
ferent course,  there  being  no  convenient  cerebrospinal  nerve  along  which  the  post- 
ganglionic fibers  may  run.  The  fibers  to  the  blood  vessels  of  the  head  leave  the  cord 
by  the  second  to  the  fourth  or  fifth  thoracic  roots  and  pass  by  the  corresponding  white 
rami  communicantes  into  the  sympathetic  chain,  up  which  they  run,  passing  through  the 
stellate  ganglion,  the  ansa  subelavii,  and  the  inferior  cervical  ganglion,  then  ascending 
in  the  cervical  sympathetic  to  the  superior  cervical  ganglion,  where  their  cell  station 
exists.  The  postganglionic  fibers  on  leaving  this  ganglion  travel  to  their  destination 
mainly  along  the  outer  walls  of  the  blood  vessels. 

The  vasoconstrictors  to  the  abdominal  viscera  are  carried  by  the  splanchnic  nerves, 
the  fibers  of  which  come  off  from  the  lower  seven  thoracic  and  the  uppermost  lumbar 


234  THE    CIRCULATION'    OF    THE    BLOOD 

roots.  The  thoracic  fibers  pass  down  the  sympathetic  chain,  which  they  leave  by  the 
great  splanchnic  nerves.  The  lumbar  fibers  form  the  lesser  or  abdominal  splanchnic 
nerves.  As  preganglionic  fibers,  therefore,  these  fibers  are  carried  by  the  greater  and 
lesser  splanchnic  nerves  into  the  abdomen,  where  the  former  comes  into  close  relation- 
ship with  the  suprarenal  glands,  giving  off  a  branch  to  the  suprarenal  ganglion.  The 
main  course  of  the  nerve  is  continued  on  to  the  solar  plexus,  in  the  various  ganglia  of 
which  most  of  the  preganglionic  fibers  end  by  synapsis,  the  postganglionic  fibers  then 
proceeding  along  the  blood  vessels  to  the  vessels  of  the  abdominal  viscera.  (See  also 
page  879). 

Vasodilator  fibers  have  a  more  varied  origin  than  vasoconstrictor,  and 
they  run  an  entirely  different  course.  Vasodilator  impulses  may  be 
transmitted  by  fibers  arising  from  practically  any  level  of  the  cerebro- 
spinal axis,  not  only  by  the  motor  roots,  but  by  the  sensory  as  well. 
Thus,  they  pass  out  of  the  spinal  cord  in  the  posterior  sacral  roots  to 
enter  the  nerves  of  the  hind  limbs,  as  has  been  demonstrated  by  observ- 
ing an  increase  in  the  volume  of  the  curarized  limb  during  electrical 
stimulation  of  the  exposed  rootlets.  The  apparent  inconsistency  of  these 
observations  Avith  the  well-known  law  concerning  the  direction  of  the 
impulses  contained  in  the  posterior  spinal  roots  is  explained  by  assum- 
ing that  the  dilator  impulses  are  transmitted  along  the  ordinary  sensory 
fibers,  since  there  are  no  efferent  fibers  in  these  roots.  They  are  impul- 
ses which  go  against  the  ordinary  stream  ( antidromic).  In  support  of 
this  explanation  it  is  of  importance  to  note  that  at  their  termination 
near  the  skin  many  sensory  fibers  split  into  several  branches,  some  of 
which  run  to  blood  vessels,  and  others  to  receptor  organs  (page  797). 
Stimulation  of  the  latter  branches  may  cause  dilatation  of  the  local  blood 
vessels  nearby,  indicating  that  impulses  must  be  transmitted  up  to  the 
point  at  which  the  branching  occurs  and  then  down  the  vascular  branch, 
this  result  being  obtained  even  after  the  main  trunk  of  the  nerve  has 
been  cut  above  the  division. 

For  the  blood  vessels  of  the  anterior  extremity,  the  vasodilator  impulses  are  similarly 
transmitted  through  the  posterior  spinal  roots  of  the  lower  cervical  region  of  the  spinal 
cord.  The  vasodilator  fibers  to  the  abdominal  viscera  are  transmitted  with  the  splanchnic 
nerves,  but  they  may  also  be  derived  from  the  posterior  spinal  roots,  for  it  has  been 
found  that  stimulation  of  posterior  roots  in  the  splanchnic  area  causes  dilatation  in  the 
intestine  (Bayliss).  Vasodilator  fibers  are  also  contained  in  the  cranial  nerves,  par- 
ticularly the  seventh  and  the  ninth,  being  distributed  in  the  former  nerve  to  the  an- 
terior portion  of  the  tongue  and  the  salivary  glands,  and  in  the  latter  to  the  posterior 
portion  of  the  tongue  and  the  mucous  membrane  of  the  floor  of  the  mouth.  The  vaso- 
dilator fillers  for  the  mucous  membrane  of  the  inside  of  the  cheeks  and  nares  have  their 
course  in  the  cervical  sympathetic,  being  distributed  to  the  buccofacial  region  in  the 
branches  of  the  fifth  cranial  nerve. 

There  is  evidence  to  show  that  the  vasodilator  fibers,  like  the  vasoconstrictor,  become 
connected  by  synapsis  with  nerve  cells  somewhere  in  their  course.  In  the  case  of  the 
vasodilator  fibers  in  the  chorda  tympani  and  nervi  erigentes,  such  cell  stations  have 
been  clearly  demonstrated  in  the  hilus  of  the  submaxillary  gland   in  the  former  nerve 


Till:    (ONTKOl;    OF    Till',    CIKCI    LATION  235 

and  iii  the  hypogastric  plexus  Bituated  on  the  aeck  of  the  bladder  in  the  latter. 
It  is  therefore  commonly  assumed  that,  although  not  recognizable  by  histologic  methods, 
such  terminal  cell  stations  must  also  exist  in  close  association  with  all  blood  vessels 
to  which  die  vasodilator  fibers  run.  Whether  or  aol  such  peripheral  cell  stations  exist, 
there  is  a  marked  difference  between  the  course  of  vasodilator  and  of  vasoconstrictor 
fibers. 

The  Vasomotor  Nerve  Centers 

Our  next  problem  is  to  trace  these  fibers  farther  into  the  central 
nervous  system,  and  find  the  location  and  study  the  characteristics  of 
the  nerve  centers  from  which  they  are  derived.  We  must  postulate  the 
existence  of  both  vasoconstrictor  and  vasodilator  centers,  but  since  there 
is  no  adequate  evidence  at  the  present  time  which  enables  us  to  locate 
the  latter,  we  must  confine  our  attention  to  the  vasoconstrictor  centers. 
These  exist  at  two  levels  in  the  cerebrospinal  axis:  (1)  in  the  gray  mat- 
ter of  the  spinal  cord,  and  (2)  in  the  gray  matter  of  the  medulla 
oblongata. 

The  spinal,  or  as  they  are  often  called,  the  subsidiary  vasoconstrictor 
centers,  are  represented  by  certain  cells  of  the  lateral  horn  of  gray  mat- 
ter in  the  thoracic  portion  of  the  spinal  cord,  from  which  the  pregan- 
glionic vasoconstrictor  fibers  above  described  are  derived.  The  exact 
location  of  the  nerve  cells  composing  the  chief  centers  in  the  medulla  has 
not  as  yet  been  definitely  made  out ;  they  undoubtedly  lie  near  those  of 
the  vagus  center  (see  Hanson).  The  axons  of  the  medullary  cells  de- 
scend in  the  lateral  columns  of  the  spinal  cord  to  end  by  synapses 
around  the  cells  of  the  subsidiary  vasoconstrictor  center  in  the  lateral 
horns. 

The  experimental  evidence  which  indicates  the  existence  of  chief  and 
subsidiary  centers  is  quite  definite.  Thus,  if  the  spinal  cord  is  cut  at  the 
lower  cervical  region  (below  the  phrenic  nuclei,  so  as  not  to  interfere 
with  the  movements  of  the  diaphragm),  the  arterial  blood  pressure  falls 
profoundly,  because  the  pathway  connecting  the  two  centers  is  broken. 
After  several  days,  however,  the  blood  pressure  will  gradually  rise  again. 
If  after  this  has  occurred,  the  spinal  cord  is  destroyed  by  pushing  a  wire 
down  the  vertebral  canal,  the  arterial  blood  pressure  will  again  fall, 
indicating  that  the  vascular  tone  which  had  been  reacquired  after  sec- 
tion of  the  pathway  between  the  main  and  the  subsidiary  centers  must 
have  been  brought  about  by  the  development  in  the  subsidiary  centers 
of  an  independent  power  of  reflex  tonic  action.  This  experiment  there- 
fore demonstrates  that  in  the  intact  animal  the  subsidiary  centers  do  not 
by  themselves  discharge  tonic  impulses.  In  other  words,  the  subsidiary 
centers  ordinarily  serve  merely  as  transfer  stations  for  the  tonic  im- 
pulses coming  from  the  chief  center,  but  when  these  impulses  no  longer 


236  THE    CIRCULATION    OF    THE    BLOOD 

arrive,  then  a  hitherto  dormant  power  of  tonic  activity  becomes  devel- 
oped in  the  subsidiary  centers. 

Independent  Tonicity  of  Blood  Vessels 

Even  after  complete  disconnection  of  the  spinal  cord  from  the  blood 
vessels,  as  by  cutting  of  the  splanchnic  nerve  to  the  abdomen  or  abla- 
tion of  that  portion  of  the  lower  spinal  cord  from  which  the  fibers  to 
the  hind  limb  arise,  the  disconnected  blood  vessels,  although  at  first 
completely  dilated,  may  later  reacquire  an  independent  tone  of  their 
own,  indicating  therefore,  that  they  must  possess  some  neuromuscular 
mechanism  which  can  act  independently  of  the  nerve  centers,  and  which 
may  be  stimulated  to  activity  by  the  presence  of  hormones  in  the  blood. 
The  hormone  wa.s  at  one  time  thought  to  be  epinephrine  (see  page  745). 

Epinephrine  control  is  indicated  in  the  effect  produced  upon  arterial 
blood  pressure  by  stimulation  of  the  great  splanchnic  nerve.  Careful 
analysis  of  the  curve,  shown  in  Fig.  29,  shows  that  the  rise  is  both  im- 
mediate and  delayed;  that  is,  the  curve  mounts  immediately,  then  flat- 
tens out  a  little,  and  then  assumes  a  further  rise.  This  delayed  response 
seems  to  depend  upon  the  excretion  of  epinephrine  into  the  blood,  for  it 
does  not  occur  when  the  suprarenal  veins  are  occluded,  and  is  much  de- 
layed by  temporarily  clamping  the  suprarenal  veins  on  the  same  side 
as  that  on  which  the  splanchnic  nerve  is  stimulated.  It  has  been  stated 
by  certain  observers  that,  after  occlusion  of  the  adrenal  veins,  there  is 
a  downward  tendency  of  the  blood  pressure,  which  however  develops 
with  extreme  slowness;  and  that  a  distinct  elevation  of  blood  pressure 
follows  the  removal  of  a  clamp  temporarily  placed  on  the  adrenal  veins. 
This  rise  is  pronounced  if  the  splanchnic  nerve  is  stimulated  during  the 
occlusion  of  the  veins.  It  must  of  course  be  understood  that  the  imme- 
diate rise  in  blood  pressure  following  splanchnic  stimulation  is  caused  by 
vasoconstriction  in  the  splanchnic  area  itself,  as  is  evidenced  by  the 
fact  that  it  does  not  occur,  or  is  only  very  faint,  when  the  abdominal 
blood  vessels  are  ligated  prior  to  the  stimulation  of  the  splanchnic  nerve. 
Even  after  ligation  of  the  adrenal  veins  and  of  the  blood  vessels  of  the 
splanchnic  area,  stimulation  of  the  splanchnic  nerve  may  still  cause  a 
slight  rise  in  arterial  blood  pressure,  possibly  because  some  fibers  may 
run  from  the  splanchnic  to  vascular  areas  not  situated  within  the  realm 
of  the  splanchnic  nerve — for  example,  the  blood  vessels  of  the  lumbar 
muscles. 


CHAPTER  XXVII 

THE  CONTROL  OF  THE  CIRCULATION  (Cont'd) 

CONTROL  OF  THE  VASOMOTOR  CENTER 

The  activities  of  the  vasomotor  center  are  controlled  partly  by  hor- 
mones and  partly  by  afferent  impulses. 

The  Hormone  Control 

As  with  the  respiratory  center,  the  chief  hormone  is  the  hydrogen-ion 
concentration  of  the  blood.  When  this  is  increased,  as  in  asphyxia,  the 
vasoconstrictor  part  of  the  vasomotor  center  becomes  stimulated,  so 
that  the  blood  vessels  are  constricted  and  the  blood  pressure  rises.  Tak- 
ing, as  our  criterion  of  hydrogen-ion  concentration,  the  tension  of  the 
carbon  dioxide  in  the  blood  (see  page  354),  we  may  proceed  to  investi- 
gate the  relationship  by  observing  the  blood  pressure  during  changes 
in  the  carbon-dioxide  tension  brought  about  by  causing  the  animal  to 
breathe  atmospheres  containing  known  percentages  of  the  gas  (Mathi- 
son15).  Thus,  if  a  decerebrate  cat  is  made  to  respire  an  atmosphere 
containing  5  per  cent  or  more  of  carbon  dioxide,  an  immediate  rise 
occurs  in  the  arterial  blood  pressure.  That  the  inhaled  carbon  dioxide 
acts  by  raising  the  hydrogen-ion  concentration  of  the  blood  is  indicated 
by  the  fact  that,  a  similar  rise  in  blood  pressure  can  be  obtained  by  intra- 
venous injection  of  a  weak  solution  of  lactic  acid  (2  c.c.  N/15)  in  a  de- 
cerebrate cat. 

Instead  of  injecting  the  lactic  acid,  we  may  cause  it  to  be  produced 
in  the  muscles  of  the  animal  itself  by  greatly  diminishing  their  oxygen 
supply.  When  a  decerebrate  cat,  for  example,  is  made  to  breathe  an 
atmosphere  of  almost  pure  nitrogen,  there  is,  after  a  latent  period  of 
about  30  seconds,  a  sudden  rise  in  arterial  pressure.  The  existence  of 
this  latent  period  in  the  latter  case,  as  compared  with  its  absence  when 
carbon  dioxide  is  inspired,  is  owing  to  the  time  taken  for  lactic  acid  to 
be  produced  in  the  muscles  on  account  of  the  oxygen  deprivation.  It 
is  important  to  note  in  the  above  experiment  that  decerebrate  animals 
are  employed  so  as  to  avoid  the  necessity  of  using  anesthesia,  under 
which  the  results  are  much  less  definite.  The  fact  that  oxygen  depriva- 
tion causes  excitation  of  the  vasoconstrictor  center  has  been  known  for 

237 


238  THE   CIRCULATION    OF   THE   BLOOD 

some  time,  but  the  explanation  that  has  usually  been  given  has  been  that 
it  is  due  to  a  direct  effect  of  oxygen  want  on  the  center. 

The  sensitivity  of  the  medullary  center  towards  the  hydrogen-ion  is 
many  times  greater  than  that  of  the  subsidiary  centers  in  the  spinal 
cord.  If  an  animal  is  kept  alive  by  artificial  respiration  for  some  time 
after  cutting  the  cervical  spinal  cord,  the  subsidiary  vasomotor  centers 
will,  as  we  have  seen,  gradually  acquire  a  tonic  action,  and  the  lowered 
blood  pressure  will  gradually  rise  again.  If,  when  this  has  been  attained, 
the  animal  is  made  to  breathe  an  atmosphere  rich  in  carbon  dioxide,  a  sud- 
den rise  in  blood  pressure  will  occur,  but  to  produce  it  a  very  much 
greater  percentage  of  this  gas  must  be  inspired  than  when  the  pathway 
between  the  chief  and  subsidiary  centers  is  intact.  Whereas  5  per  cent 
carbon  dioxide  is  sufficient  to  cause  a  rise  of  pressure  in  an  animal  hav- 
ing its  chief  vasomotor  center,  it  takes  25  per  cent  and  upward  to  pro- 
duce a  like  effect  on  a  spinal  animal:  and  similarly,  although  2  c.c.  of 
N/15  lactic  acid  will  stimulate  the  chief  vasomotor  center,  it  takes  5  c.c. 
of  N  2  to  excite  the  spinal-cord  centers. 

The  Nerve  Control 

However  important  hormones  may  be  in  maintaining  a  tonic  stimula- 
tion of  the  center,  the  more  sudden  changes  in  activity  are  mainly 
brought  about  by  afferent  nerve  impulses.  The  afferent  impulses  are 
of  two  classes:  (1)  those  causing  a  rise  in  blood  pressure,  called 
pressor,  and  (2)  those  causing  a  fall  in  blood  pressure,  called  depressor. 
The  effect  produced  on  the  arterial  blood  pressure  by  stimulation  of 
either  pressor  or  depressor  fibers  is  usually  more  or  less  evanescent, 
especially  in  the  case  of  the  depressor  fibers ;  and  when  the  change  f  ol- 
lowing  stimulation  of  the  nerve  passes  off,  the  blood  pressure  always 
returns  to  its  former  level.  This  indicates  that  the  afferent  impulses  do 
not  affect  the  tonic  control  which  the  vasomotor  center  exercises  on  the 
blood  vessels.  It  has,  therefore,  been  assumed  by  Porter10  that  there  are 
really  two  kinds  of  vasomotor  centers:  one  concerned  merely  in  the 
bringing  about  of  temporary  reflex  changes,  the  other  concerned  in  the 
maintenance  of  the  vascular  tone.  It  may  be  that  the  activities  of  the 
former  are  primarily  dependent  upon  afferent  impulses,  and  the  latter, 
upon  hormones.  Justification  for  this  view  has  been  found  in  observa- 
tions made  on  the  effects  of  stimulation  of  pressor  and  depressor  fibers 
in  animals  under  the  influence  of  curare  or  alcohol.  "With  the  former 
drug,  stimulation  of  a  nerve  containing  a  preponderance  of  pressor  or 
depressor  fibers  produces  double  its  usual  effect,  but  the  mean  level  of 
the  blood  pressure  apart  from  this  effect  remains  unchanged.  With  the 
latter  drug  (alcohol),  on  the  other  hand,  the  reflex  response  entirely 


THE   CONTROL   OP   THE   CIRCULATION  239 

disappears,  although  it  immediately  reappears  when  the  alcohol  effecl 

has  passed  off,  and  there  is  no  evidence  of  a  change  in  tone.    The  tonic 
and  the  reflex  mechanisms  of  the  vasomotor  center  can  not  therefore  be 

identical. 

At  the  present  stage  of  our  knowledge,  it  is  only  possible  for  us  to 
study  the  effect  of  stimulation  of  pressor  and  depressor  fibers  on  the 
vasoreflex  center.  Such  filters  are  contained  in  practically  every  sen- 
sory nerve  of  the  body,  and  it  would  appear  that  a  fairly  equal  mixture 
of  both  kinds  of  fiber  exists  in  most  of  these  nerves. 

Pressor  and  Depressor  Impulses. — Depressor  impulses  are  alone  present 
in  the  cardiac  depressor  nerve.  Sometimes  as  in  the  rabbit,  this  exists 
as  an  independent  nerve  trunk,  originating  by  two  branches,  one  from 
the  superior  laryngeal,  the  other  from  the  vagus,  and  descending  close  to 


Fig.  73. — Fall  of  blood  pressure  from  excitation  of  the  depressor  nerve.  The  drum  was 
stopped  in  the  middle  of  the  curve  and  the  excitation  maintained  for  seventeen  minutes.  The  line 
of  zero   pressure   should   be   30   mm.   lower  than   here   shown.      (From   Bayliss.) 

the  vagus  trunk,  to  end  around  the  arch  of  the  aorta.  In  other  animals 
the  depressor  is  bound  up  with  the  vagus  trunk  from  which  it  can  some- 
times be  separated  by  careful  dissection.  The  first  prerequisite  in  inves- 
tigating the  cause  of  the  changes  produced  by  stimulation  of  these  nerves 
is  the  elimination  of  any  chance  of  an  alteration  in  heartbeat  as  a  result 
of  simultaneous  stimulation  of  afferent  vagus  fibers.  This  may  be  done 
either  by  cutting  both  vagi  or  by  administering  atropine. 

Stimulation  of  the  central  end  of  the  cardiac  depressor  nerve  in  such 
an  animal  causes  an  immediate  fall  in  blood  pressure,  accompanied  by  an 
increase  in  volume  which  can  be  demonstrated  either  in  the  hind  limb  or  in 
one  of  the  abdominal  viscera — evidence  of  general  vasodilatation  (Fig.  73). 

When  the  central  end  of  a  sensory  nerve,  such  as  the  sciatic,  is  acted 
on  by  a  stimulus  of  moderate  strength,  it  will  usually  be  found  that  the 
arterial  blood  pressure  rises  and  that  the  volume  of  the  limb  or  of  some 


240  THE    CIRCULATION   OF    THE   BLOOD 

abdominal  viscus  becomes  diminished — evidence  of  general  vasoconstric- 
tion. But  when  the  sensory  nerve  is  stimulated  with  extremely  weak 
faradic  shocks,  an  entirely  different  result  is  likely  to  be  obtained; 
namely,  a  fall  of  blood  pressure  and  an  increase  in  volume  of  the  limb 
or  viscus,  indicating  that  in  this  manner  we  have  stimulated  depressor 
fibers.  By  careful  experimentation  with  quantitatively  graduated  elec- 
trical stimuli,  it  has  been  found  by  Martin  and  others17  that  on  stimu- 
lating an  afferent  nerve  with  weak  shocks,  a  fall  in  blood  pressure  is 
the  first  effect  to  be  observed,  and  that  this  becomes  more  and  more 
marked  as  the  strength  of  the  stimuli  is  increased,  until  a  certain  opti- 
mum is  reached,  after  which  the  fall  in  blood  pressure  becomes  less  evi- 
dent. When  a  certain  strength  of  stimulation  is  exceeded,  a  rise  instead 
of  a  fall  occurs.  After  this  point  additional  increase  in  stimulation  causes 
more  and  more  marked  elevation  of  blood  pressure  through  a  very  long 
range  of  stimuli. 

Stimulation  of  two  afferent  nerves  at  the  same  time  usually  produces 
a  greater  reflex  vasomotor  change  than  the  stimulation  with  an  equiva- 
lent strength  of  current  of  either  nerve  alone.  That  is  to  say,  the  effect 
produced  by  stimulating  the  central  end  of  both  sciatics  simultaneously 
will  be  greater  than  that  produced  by  stimulating  either  alone  with  double 
the  strength  of  stimulus. 

As  has  been  stated  above,  the  reflex  change  in  blood  pressure  is  often 
quite  transitory  in  nature,  although  the  stimulation  of  the  pressor  nerve  is 
maintained.  When  this  decline  has  occurred,  the  pressor  reaction  can 
often  be  renewed  by  shifting  the  stimulation  to  a  second  nerve.  These 
facts  concerning  the  greater  efficacy  of  combined  stimulation  of  several 
nerves  are  of  considerable  importance  in  connection  with  the  general 
question  of  reflex  changes  in  blood  pressure.  For  instance,  many  of  the 
pressor  fibers  found  in  the  sciatic  nerve  are  connected  with  the  receptors 
that  mediate  the  sensations  of  the  skin.  When  these  receptors  are 
stimulated,  as  by  heat  or  cold,  reflex  changes  in  blood  pressure  occur 
(pressor  reaction),  (Fig.  74),  and  it  is  important  to  remember  that 
localized  stimulation  of  the  skin  is  less  efficient  in  bringing  about  such 
vascular  changes  than  stimulation  applied  over  large  areas,  even  when 
the  local  stimulus  is  intense  and  the  general  stimulus  mild  in  character. 
Jumping  into  a  moderately  cold  bath  will  cause  a  much  greater  rise  in 
arterial  blood  pressure  than  plunging  the  hand  into  ice  cold  water. 

Mechanism  of  Action  of  Pressor  and  Depressor  Impulses. — When  we 
consider  the  exact  mechanism  by  which  these  afferent  impulses  operate, 
we  have  to  bear  in  mind  four  possibilities:  the  reflex  fall  produced  by 
stimulation  of  a  depressor  afferent  fiber  may  be  due  either  to  a  stimula- 
tion of  the  vasodilator  part  of  the  center  or  to  an  inhibition  of  the  tone 


TIIK    CONTUOl,    OK    Till:    CIRCULATION 


241 


ol  the  vasoconstrictor  part;  and,  conversely,  a  rise  in  arterial  pressure 
caused  by  vasoconstriction  may  be  dependent  cither  on  a  stimulation  of 
the  vasoconstrictor  part  of  the  center  or  on  an  inhibition  of  the  tone  of 
the  vasodilator  part.  All  of  these  changes  have,  as  a  matter  of  fact,  been 
shown  to  occur,  at  least  under  certain  conditions,  although  the  evidence 


Fig.  74. — The  effect  of  strong  stimulation  (heat)  of  the  skin  of  the  foot  on  the  arterial  blood 
pressure  and  respiratory  movements.  Upper  tracing,  thoracic  movement;  lower  tracing,  arterial 
blood    pressure. 

for  the  inhibition  of  dilator  tone  is  as  yet  a  little  uncertain  (see  Fig.  75). 
Without  going  into  the  subject  in  detail,  we  may  nevertheless  take 
as  an  example  of  the  methods  by  which  the  information  has  been  ob- 
tained, the  experiment  performed  by  Bayliss,18  showing  that  the  vasodi- 
lation which  results  from  stimulation  of  the  depressor  nerve  is  owing 
partly  to   removal   of  vasoconstrictor   tone   and   partly   to   vasodilator 


242 


THE    CIRCULATION    OF    THE    BLOOD 


stimulation.  The  volume  of  the  hind  limb  of  a  curarized  and  vagotomized 
rabbit  increases  when  the  central  end  of  the  cardiac  depressor  nerve  is 
stimulated.  In  order  to  determine  whether  this  dilatation  is  due  solely 
to  the  removal  of  vasoconstrictor  tone,  the  above  experiment  was  repeated 
on  a  rabbit  in  which  the  sympathetic  chain  had  been  cut  below  the  level 
of  the  second  lumbar  spinal  roots.  By  such  an  operation  all  the  vaso- 
constrictor fibers  to  the  vessels  of  the  hind  limb  are  severed,  but  the 
vasodilator  fibers,  since  they  emanate  through  the  sacral  sensory  roots, 
are  left  intact.  It  Mas  nevertheless  found  on  stimulating  the  depressor 
nerve  that  dilatation  of  the  hind  limb  still  occurred,   thus  indicating 


Fig.    75.- — Diagram    showing   the   probable    arrangements   of    tht    vasomotor    reflexes. 

A.  Muscle   of   arteriole. 

D.  Vasodilator  nerve  fiber  terminating  on  A  and  inhibiting  its  natural  tonus,  as  indicated  by  - 
sign. 

D.  Vasoconstrictor  fiber  also  ending  in  A,  but  exciting  it  (x).  These  two  kinds  of  fiber  arise 
from    the    dilator    center    (DC)    and    the    constrictor    center    (CC)    respectively. 

F.  Afferent  depressor  fiber,  dividing  into  two  branches,  one  of  which  (-)  inhibits  the  con- 
strictor center,  while  the  other  (+)  excites  the  dilator  center  causing  dilatation  of  the  arteriole  and 
fall  of  blood  pressure. 

R.  Pressor  fiber  exciting  CC  and  inhibiting  DC,  and  therefore  causing  vasoconstriction  and  rise 
of  blood  pressure. 

a,  b,  c,  and  d  represent  the  synapses  of  the  pressor  and  depressor  branches  with  the  efferent 
neurons.      (From   Bayliss.) 

that  stimulation  through  vasodilator  fibers  must  have  taken  place.  Con- 
versely, in  another  experiment,  instead  of  the  sympathetic  chain,  the 
spinal  cord  was  cut  below  the  level  of  the  second  lumbar  segment,  thus 


Till:   CONTROL   OF   THE   CIRCULATION  243 

Bevering  the  dilator  lmi  qo1  the  constrictor  path,  and  again  depressor 

stimulation  caused  the  volume  of  the  limb  to  increase,  indicating  thai 
an  inhibition  of  constrictor  tone  must  have  occurred. 

Reciprocal  Innervation  of  Vascular  Areas 

It  must  not  be  imagined  thai  changes  in  the  caliber  of  the  blood  ves- 
sels occurring  in  one  vascular  area  are  necessarily  occurring  all  over 
the  body.  On  the  contrary,  a  most  important  reciprocal  'relationship 
exists  in  the  blood  supply  to  different  parts.  After  food  is  taken,  for 
example,  more  blood  is  required  by  the  digestive  organs  than  when  they 
are  at  rest,  and  this  is  insured  by  dilatation  of  their  own  vessels  along 
with  reciprocal  constriction  of  those  of  other  parts  of  the  body.  On 
account  of  the  relatively  great  capacity  of  the  abdominal  vessels,  their 
dilatation  during  digestive  activity  is  usually  greater  than  the  reciprocal 
constriction  of  the  other  vessels,  so  that  the  diastolic  blood  pressure  falls, 
necessitating  a  more  powerful  cardiac  discharge  in  order  to  maintain 
the  mean  pressure.  After  taking  food,  the  systolic  pressure  does  not 
as  a  rule  fall  so  much  as  the  diastolic,  if  it  falls  at  all;  and  the  pres- 
sure pulse  therefore  becomes  greater  and  causes  a  greater  live  load  to 
be  applied  to  the  vessels  with  each  heartbeat.  During  the  sudden  strain 
that  is  thrown  on  them,  weakened  arteries  may  give  way,  especially  in 
the  brain. 

Another  example  of  reciprocal  action  of  the  vascular  system  is  seen 
in  muscular  exercise.  The  vessels  of  the  active  muscles  dilate,  while 
those  elsewhere  constrict.  The  local  dilatation  in  this  case  is,  however, 
not  entirely  at  least  a  nervous  phenomenon,  being  caused  in  fact,  as  we 
shall  see,  by  hormone  action  on  account  of  the  local  increase  in  hydro- 
gen-ion concentration  (sec  page  414).  There  can  be  little  doubt  that 
local  irritants  to  the  surface  of  the  body,  such  as  hot  applications,  lini- 
ments, etc.,  act  in  the  same  way;  they  cause  local  dilatation  of  the  super- 
ficial and  perhaps  of  the  immediately  underlying  vessels  and  constric- 
tion of  those  elsewhere  in  the  body.  Application  of  cold  to  local  areas 
of  skin  similarly  causes  local  constriction  accompanied  by  reciprocal 
dilatation  elsewhere.  This  action  of  cold  is  very  marked  in  some  parts  of 
the  body,  such  as  the  hands,  where  by  Stewart's  method  (page  283)  it 
can  be  shown,  not  only  that  the  bloodflow  of  the  hand  to  which  the  cold 
is  applied  is  greatly  curtailed,  but  also  that  of  the  opposite  side. 

Experimental  demonstration  of  reciprocal  vascular  innervation  is  fur- 
nished by  numerous  experiments.  If  the  central  end  of  the  great  auric- 
ular nerve  of  the  ear  is  stimulated  in  a  rabbit,  a  blanching  of  the  ves 
sels  of  the  ear  occurs  at  the  same  time  as  a  rise  in  arterial  blood  pres- 


244  THE    CIRCULATION    OF    THE   BLOOD 

sure  (Loven  reflex).     Similarly  when  the  central  end  of  one  of  the  sen- 
ary roots  of  the  leg  of  a  dog  is  stimulated,  there  is  a  rise  in  arterial 
blood  pressure  and  an  increase  in  the  volume  of  the  limb. 

THE  INFLUENCE  OF  GRAVITY  ON  THE   CIRCULATION 

If  the  arterial  blood  pressure  is  measured  in  the  arm  and  leg  in  a  man 
standing  erect,  a  difference  corresponding  to  the  hydrostatic  effect  of 
gravity  will  be  found  between  the  two  readings.  In  comparison  with 
the  high  pressure  normally  existing  in  the  arteries,  this  difference  is, 
however,  of  little  significance.  On  the  other  hand,  in  the  veins,  where 
the  average  pressure  is  low,  gravity  would  cause  serious  embarrassment 
to  the  circulation  of  blood  were  it  not  for  the  valves  and  the  forces 
which  move  the  blood  beyond  them  (page  214). 

In  erect  animals  the  part  of  the  circulation  in  which  blood  might  stag- 
nate as  a  result  of  gravity  is  the  splanchnic  area.  Were  such  stagna- 
tion to  occur,  the  blood  would  not  be  returned  to  the  right  heart,  so 
that  the  arteries  would  not  receive  sufficient  blood  to  maintain  an  ade- 
quate circulation,  particularly  in  the  vessels  of  the  brain. 

Simple  experiments  devised  by  Leonard  Hill19-  zs  illustrate  these  prin- 
ciples. "When  a  snake,  for  example,  is  pinned  out  on  a  long  piece  of 
wood  and  an  opening  made  opposite  the  heart,  this  organ  can  be  seen 
to  fill  adequately  with  blood  as  long  as  the  animal  is  maintained  in  the 
horizontal  position.  \Yhen  placed  vertically,  however,  the  heart  be- 
comes bloodless.  If  now  the  tail  end  of  the  animal  is  placed  in  a  cylinder 
of  water  so  as  to  overcome  the  effect  of  gravity,  the  heart  will  be  seen 
to  fill  again  with  blood.  Evidently  in  such  an  animal  there  is  no  mechan- 
ism to  compensate  for  gravity. 

If  a  domestic  rabbit  with  a  large  pendulous  abdomen  is  held  in  the 
vertical  tail-down  position,  stagnation  of  blood  in  the  splanchnic  ves- 
sels occurs  to  such  an  extent  that  in  from  fifteen  to  twenty  minutes  the 
animal  dies  from  cerebral  anemia.  If  an  abdominal  binder  is  first  of  all 
applied,  the  vertical  position  will  not  have  the  same  consequences.  This 
experiment  illustrates  clearly  the  possible  evil  effects  that  gravity  may 
produce  in  animals  in  which  no  mechanism  exists  to  compensate  for  it. 

Placing  an  animal  such  as  a  dog  under  light  ether  anesthesia  in  the 
vertical  tail-down  position  produces  an  immediate  fall  in  arterial  blood 
pressure,  as  shown  in  the  tracing  (Fig.  76),  followed  by  a  certain  de- 
gree of  compensation  even  while  the  animal  is  still  in  the  erect  position. 
The  extent  to  which  this  compensation  occurs  varies  with  the  depth  of 
the  anesthesia.  If  the  experiment  is  repeated  after  administering  a  large 
dose  of  chloroform,  not  only  will  the  initial  fall  be  much  greater,  but 


THE    CONTROL   OF    THE    CIRCULATION  245 

subsequent  compensation  will  he  practically  absent.     The  application  of 
these  facts  in  the  operating  room  will  be  self-evident. 

Leonard  Hill  has  shown  that  three  factors  are   involved   in  the  com- 
pensating mechanism:   (1)    the  tonicity  of  the  abdominal  musculature; 


Fig.    76. — Aortic    blood    pressure,    showing    the    effect    of    posture:      A,    vertical,    head-up;    B,    hori 
zontal;     C,    vertical,    head-down;    D,    horizontal.       (L.H.) 

(2)  the  tone  of  the  splanchnic  blood  vessels;  (3)  the  pumping  action  of 
the  respiratory  movements.  The  importance  of  the  first-mentioned  fac- 
tor can  be  readily  shown  by  making  a  crucial  incision  of  the  abdom- 
inal -walls  in  an  animal  in  the  erect  position   (Fig.   77),   and  that   of 


Fig.  77. — Tracing  to  show  the  effect  of  gravity  on  the  arterial  blood  pressure.  At  A,  the 
animal  was  placed  in  the  vertical  position;  at  B,  the  abdomen  was  compressed;  at  C,  a  crucial 
incision  was  made  in  the  abdomen;  at  D,  the  pleural  cavity  was  opened;  at  F,  the  animal  was 
returned    to    the    horizontal    position.      (From    Leonard    Hill.) 

the  second  factor  by  cutting  the  great  splanchnic  nerves,  or  the  spinal 
cord.  After  such  an  operation,  even  while  in  the  horizontal  position,  as 
we  have  seen,  the  blood  pressure  falls  to  a  considerable  extent.  If  the 
animal  is  now  placed  in  the  vertical  tail-down  position,  however,  it  falls 


246 


THE    CIRCULATION    OF    THE   BLOOD 


to  the  zero  line  and  the  animal  soon  dies  (Fig.  78).  The  influence  of  the 
third  factor  is  not  so  great  as  of  the  other  two,  but  can  be  shown  by  the 
increased  respiratory  activity  which  is  likely  to  develop  in  the  vertical 


Fig.  78. — The  effect  of  gravity  on  the  aortic  pressure  after  division  of  the  spinal  cord  in  the 
upper  dorsal  region.  By  placing  the  animal  in  the  vertical  feet-down  posture,  the  pressure  fell 
almost  to  zero,  but  on  returning  it  to  the  horizontal  posture,  the  circulation  was  restored.  (From 
Leonard   Hill.) 

tail-down  position,  the  anemic  condition  of  the  respiratory  center  being 
no  doubt  the  cause  of  the  increased  respiration. 


CHAPTER  XXVIII 

PECULIARITIES  OF  BLOOD  SUPPLY  IN  CERTAIN  VISCERA 

Up  to  the  present  we  have  been  considering  the  circulation  of  the  blood 
from  a  general  point  of  view.  There  are  certain  organs  and  tissues,  how- 
ever, in  which  the  general  mechanism  is  altered  in  order  to  meet  pecu- 
liar requirements  of  blood  supply.  Thus,  it  is  evident  that  the  brain, 
incased  as  it  is  in  the  rigid  cranium,  will  be  unable  to  contract  and 
expand  as  a  result  of  vasoconstriction  or  vasodilation.  On  the  other 
hand,  we  know  that  the  blood  supply  to  this  organ  does  vary  con- 
siderably from  time  to  time.  What  is  the  nature  of  the  mechanism  by 
which  such  changes  are  brought  about?  In  the  case  of  the  liver  the  cir- 
culation is  peculiar  on  account  of  the  fact  that  blood  is  carried  to  the 
organ  by  two  vessels,  in  one  of  which  it  is  supplied  under  high  pressure 
and  in  the  other,  under  low  pressure.  We  must  investigate  the  rela- 
tionship of  these  two  sources  of  blood  supply.  The  circulation  through 
the  coronary  and  pulmonary  vessels  must  likewise  receive  special  atten- 
tion on  account  of  the  highly  specialized  functions  of  these  organs. 

THE  CIRCULATION  IN  THE  BRAIN 

Anatomic  Peculiarities 

Serious  curtailment  of  the  blood  supply  to  the  brain  is  guarded  against 
by  the  existence  of  the  circle  of  Willis.  Besides  the  four  main  arteries — 
the  vertebrals  and  the  two  carotids — the  spinal  arteries  contribute  to 
the  blood  supply  of  the  circle,  and  consequently  in  certain  animals,  such 
as  the  dog,  the  four  main  arteries  may  be  ligated  without  causing  death. 
In  man,  however,  ligation  of  both  carotids  is  usually  fatal.  The  free 
anastomosis  displayed  in  the  circle  of  Willis  is  not  maintained  in  the 
case  of  the  arteries  which  run  from  it  to  supply  the  brain  structure.  On 
the  contrary,  these  vessels  are  more  or  less  terminal  in  character;  that 
is  to  say,  the  capillary  system  produced  by  the  different  vessels  does  not 
freely  anastomose,  so  that  the  obstruction  of  one  vessel,  or  an  important 
branch,  is  followed  by  death  of  the  supplied  area.  The  vessels  which  go 
to  the  pia  mater,  however,  break  up  into  numerous  smaller  branches, 
which  freely  anastomose  before  entering  the  brain  tissue. 

247 


248 


THE    CIRCULATION    OF    THE   BLOOD 


The  venous  blood  is  collected  by  the  small,  very  thin-walled  and  valve- 
less  cerebral  veins.  These  run  together  to  form  larger  veins  dis- 
charging into  the  sinuses,  the  openings  into  which  are  kept  patent  by 
the  arrangement  of  dura  mater  around  the  orifices.  The  sinuses  exist 
between  the  dura  and  skull  and  are  so  constructed  that  they  can  not 
be  compressed,  particularly  those  at  the  base  of  the  brain.  From  them 
the  blood  is  conveyed  mainly  to  the  internal  jugular  vein,  some  of  it 
however  escaping  by  the  anastomoses  existing  between  the  cavernous 
sinus  and  the  opththalmic  veins,  and  by  the  venous  plexus  of  the  spinal 
cord.  The  most  striking  peculiarities  of  the  veins  are  their  patulous  con- 
dition and  the  absence  of  valves,  so  that  any  change  in  the  blood  pres- 
sure in  the  internal  jugular  vein  must  be  immediately  reflected  in  that  of 
the  venous   sinuses.     This  explains  why  compression   of  the   abdomen 


Fig.  79. — Schema  to  show  the  relations  of  the  Pacchionian  bodies  to  the  sinuses:  d,  d.  Folds 
of  the  dura  mater,  inclosing  a  sinus  between  them;  v.b.,  the  blood  in  the  sinus;  a,  the  arachnoidal 
membrane;  p,  the  pia  mater;  Pa.,  the  Pacchionian  body  as  a  projection  of  the  arachnoid  into  the 
blood  sinus.      (From   Howell's  Physiology.) 

causes  venous  blood  to  flow  from  an  opening  made  in  the  longitudinal 
sinus. 

In  considering  the  cerebral  circulation,  another  factor  that  must  be 
borne  in  mind  is  the  presence  of  cerebrospinal  fluid.  This  is  contained 
hi  the  subarachnoid  spaces  of  the  brain  and  spinal  cord,  these  spaces,  in 
the  case  of  the  brain,  being  often  considerably  enlarged  to  form  the 
cisternal.  The  cerebrospinal  fluid  is  also  present  in  the  ventricles  of  the 
brain,  which  it  will  be  remembered  communicate  with  the  subarachnoid 
spaces  through  the  foramen  of  Magendie,  etc.  It  is  unlikely  that  the 
cerebrospinal  fluid  is  of  much  importance  in  connection  with  the  control 
of  the  blood  supply  to  the  brain  tissue.  It  may  be  merely  a  lubricating 
fluid;  at  least  it  is  so  small  in  amount  (60  to  80  c.c.  in  man)  as  to  be 
apparently  of  little  value  in  bringing  about  an  alteration  in  brain  volume. 


Peculiarities  of  blood  supply  in  certain  viscera  249 

Although  normally  bo  scanty,  its  secretion  can  become  remarkably  stim- 
ulated under  certain  conditions  as  in  fractures  of  the  base  of  the  skull. 
Under  these  conditions  in  man,  it  may  drain  away  at  the  rate  of  aboul 
200  e.e.  a  day  or  more. 

The  fluid  is  apparently  secreted  from  the  choroid  plexus,  for  when 
the  pathways  by  which  the  ventricles  communicate  with  the  subarach- 
noid space  are  obstructed,  it  collects  in  the  ventricles,  producing-  internal 
hydrocephalus.  Under  certain  conditions  its  absorption  is  also  very 
rapid,  as  shown  experimentally  by  the  rapidity  with  which  physiologic 
saline  is  absorbed  when  it  is  injected  into  the  subarachnoid  space.  This 
absorption  is  believed  to  occur  through  the  Pacchionian  bodies,  which 
are  minute  sac-like  protrusions  of  the  arachnoid  into  the  interior  of  a 
venous  sinus.  The  membrane  that  separates  blood  and  cerebrospinal 
fluid  is  extremely  thin  at  these  places  (Fig.  79). 

Physical  Conditions  of  Circulation 

On  account  of  these  anatomic  peculiarities,  the  physical  factors  con- 
trolling the  circulation  of  blood  to  the  brain  are  considerably  different 
from  those  obtaining  in  any  other  part  of  the  body,  with  the  possible 
exception  of  the  bones.  In  other  vascular  areas,  we  have  seen  that,  when 
dilatation  or  constriction  of  the  vessels  occurs,  a  marked  increase  or 
diminution  of  the  volume  of  the  part  becomes  evident.  Such  a  change 
in  volume  is  evidently  impossible  in  the  case  of  the  brain  because  of 
the  rigid  cranium  in  which  it  is  contained.  In  fact,  from  a  physical 
point  of  view  we  must  consider  the  blood  vessels  of  the  brain  as  pro- 
jecting into  a  rigid  case  filled  with  incompressible  material.  Under 
these  conditions  it  is  obvious  that  the  vessels  as  a  whole  could  neither 
contract  nor  dilate  without  some  increase  or  decrease  in  the  volume  of 
the  contents  of  the  cranial  cavity  (Leonard  Hill10). 

Some  have  thought  that  the  cerebrospinal  fluid  as  it  flows  into  or  out 
of  the  spinal  cord  might  accomplish  this  alteration  in  the  cranial  con- 
tents, but  the  relatively  small  amount  of  available  cerebrospinal  fluid, 
the  smallness  of  the  openings  between  the  brain  and  the  spinal  cord,  and 
the  lack  of  experimental  evidence  that  such  changes  in  volume  of  cere- 
brospinal fluid  in  the  spinal  cord  do  actually  occur,  all  stand  in  contra- 
diction to  such  a  view.  However,  although  the  vessels  as  a  whole  might 
not  contract  or  expand,  yet  some  vessels,  like  the  arteries,  might  con- 
tract simultaneously  with  a  corresponding  dilatation  of  other  vessels, 
such  as  the  smaller  cerebral  veins.  In  admitting  the  possibility  of  some 
reciprocal  relationship  between  arteries  and  veins,  we  must  remember 
that  it  is  only  before  the  well-protected  sinuses  are  reached  that  a 
change  in  the  caliber  of  the  veins  would  be  possible.    But  it  is  difficult 


250  THE    CIRCULATION   OF    THE   BLOOD 

to  see  how  such  reciprocal  dilatation  and  constriction  could  be  of  any 
advantage  except  perhaps  in  causing  certain  areas  to  receive  more 
blood  than  others.  A  reciprocal  relationship  might  also  exist  between 
adjacent  arterioles  as  well  as  between  arterioles  and  veins;  when,  for 
example,  the  arm  center  becomes  active,  it  is  conceivable  that  its 
arterioles  might  dilate  at  the  same  moment  that  those  of  a  neighboring, 
less  active  center  become  constricted.  Alterations  obviously  might  oc- 
cur without  causing  any  perceptible  change  either  in  the  volume  of  the 
brain  as  a  whole  or  in  the  condition  of  venous  flow. 

In  consideration  of  these  factors,  most  observers  are  agreed  that  the 
total  volume  of  blood  in  the  brain  must  be  constant  at  all  times  (Monro 
and  Kellie  doctrine).  Alteration  of  blood  supply  can,  however,  still  be 
brought  about  by  changes  in  the  velocity  with  which  the  blood  traverses 
the  vessels.  When  more  blood  is  required  in  the  brain  to  supply  the 
increased  metabolism  which  we  must  presume  accompanies  heightened 
mental  activity,  it  is  not  accomplished  as  in  other  parts  of  the  body  by 
an  increase  in  the  capacity  of  the  vessels  as  compared  with  those  of 
other  vascular  areas,  but  by  a  hurrying  up  of  the  circulation  through 
vessels  whose  caliber  remains  unaltered. 

The  main  factors  determining  the  velocity  of  bloodflow  through  the 
drain  mast,  therefore,  be  dependent  upon  changes  occurring  elsewhere 
in  the  vascular  system,  a  conclusion  for  which  there  is  abundant  experi- 
mental evidence.  Of  the  many  ingenious  methods  that  have  been  de- 
vised to  secure  this  evidence,  we  will  cite  but  one  in  this  place.  Records 
are  taken  of  changes  in:  (1)  the  venous  blood  pressure  of  the  brain  by 
connecting  a  cannula  either  with  the  vein  immediately  after  leaving  the 
skull  or,  better  still,  with  the  torcular  Herophili;  (2)  the  brain  volume, 
by  connecting  a  very  sensitive  receiving  tambour  with  a  trephine  hole 
in  the  cranium  so  that  its  open  end  lies  against  the  pia  mater.*  Al- 
though, as  we  have  seen,  Avhile  incased  in  the  rigid  cranium  the  brain 
volume  can  not  change  to  any  degree,  yet  this  will  occur  when  a 
portion  of  the  cranium  is  removed,  so  that  pulsations  correspond- 
ing to  those  in  the  blood  vessels  will  be  observed;  (3)  the  circula- 
tory conditions  elsewhere  in  the  body,  by  taking  arterial  and 
venous  pressures  and  plethysmograms.  The  results  in  a  normal  an- 
imal show  the  folloAving  points  (see  Fig.  80):  (1)  The  tracings  of 
the  arterial  blood  pressure  (A),  the  brain  volume  (0)  and  the  intra- 
cranial venous  pressure  (C)  have  exactly  the  same  contour — that  is, 
the  respiratory  and  the  cardiac  waves  in  all  three  of  them  are  identical. 
The  venous  blood  as  it  flows  into  the  jugular  veins   also  pulsates  in 


*This  receiving  tambour  really  consists  of  a  brass  tube  of  the  same  diameter  as  the  trephine 
hole,  into  which  it  is  tightly  fitted.  The  brass  tube  is  closed  at  its  inner  end  by  thin  rubber  membrane, 
and  its  outer  end  is  connected  with  the  receiving  tambour. 


PECULIARITIES   OF   BLOOD   SUPPLY    IN    CERTAIN   VISCERA  251 

unison  with  the  artery.  (2)  Any  change  in  the  blood  pressure  of  the 
systemic  venous  system  is  immediately  reflected  in  the  blood  pressure 
of  the  sinuses  of  the  brain  and  in  the  brain  volume  (not  well  shown  in 
accompanying  tracing).  (3)  A  change  never  occurs  in  the  vessels  of 
the  brain  which  can  not  be  accounted  for  by  some  change  occurring 


pig-  80. — To  show  simultaneous  records  of  the  arterial  blood  pressure  (A),  the  venous  pres- 
sure (B),  the  intracranial  pressure  (C),  the  pressure  in  the  venous  sinuses  (D).  The  fall  in  ar- 
terial pressure  produced  by  stimulation  of  the  cerebral  end  of  the  vagus  will  be  found  to  cause 
a  fall  of  intracranial  and  cerebral  venous  pressure,  accompanying  that  in  the  arteries,  but  a  rise 
in   that  of  the  venous  system.      (From    Leonard   Hill.) 

elsewhere  in  the  vascular  system  outside  the  cranial  cavity.  This  re- 
sult is  important  because  it  shows  that  there  can  not  be  vasomotor 
nerve  control  of  the  brain  vessels. 

Taking  into  consideration  not  only  the  results  of  such  experiments, 
but  also  the  peculiar  physical  conditions  existing  in  the  cranial  cavity, 


252  THE    CIRCULATION    OF    THE    BLOOD 

we  must  conclude  that  changes  in  blood  supply  depend  on  changes  in 
the  velocity  of  the  bloodflow,  and  that  such  alterations  in  velocity  are 
dependent  upon  changes  occurring  in  the  aortic  and  more  especially 
in  the  vena-cava  pressure.  When  the  aortic  pressure  rises,  more  blood 
will  floAv  into  the  cerebral  arteries  and  move  along  them  at  an  increased 
velocity,  the  increased  pressure  probably  causing  a  moderate  degree 
of  passive  dilatation,  to  allow  extra  room  for  which  the  numerous 
small  cerebral  veins  become  compressed.  This  compression  of  the  veins 
probably  does  not  obstruct  the  greater  flow  of  blood  through  them,  be- 
cause, taken  as  a  whole,  they  are  ordinarily  much  more  capacious  than 
need  be.  On  the  other  hand,  if  the  aortic  pressure  should  remain  con- 
stant, but  that  in  the  vena  cava  increase,  then  there  would  be  obstruc- 
tion to  the  passage  of  blood  in  the  intracranial  arteries,  and  conse- 
quently a  diminished  velocity  of  flow. 

Vasomotor  Nerves 

It  might  be  inferred  that,  since  the  bloodflow  through  the  cerebral 
vessels  is  mainly  dependent  on  vascular  conditions  elsewhere  in  the 
body,  there  would  be  no  need,  as  in  the  vessels  of  other  vascular  areas, 
for  vasomotor  fibers.  Histologists  have,  however,  discovered  the  pres- 
ence of  such  fibers,  and  it  has  become  necessary  for  the  physiologist  to 
find  out  if  they  are  really  of  importance  in  connection  with  the  regula- 
tion of  the  blood  supply  to  the  brain.  Even  if  it  is  admitted  that  the 
arterioles  could  not  contract  or  expand  as  a  whole  without  producing 
local  changes  in  venous  pressure  or  cranial  volume,  it  is  yet  of  course 
always  possible,  as  has  already  been  pointed  out,  that  one  set  of  arte- 
rioles might  contract  at  the  same  moment  that  another  set  expanded. 

That  the  vessels  can  undergo  a  process  of  constriction  has  been  shown 
by  experiments  in  which  the  volume  of  outflow  from  the  vessels  of 
the  brain  was  measured  in  perfused  preparations  of  brain.  "When 
epinephrine  was  added  to  the  perfusion  fluid,  curtailment  of  outflow 
was  observed  to  occur  (Wiggers).  Since  this  drug  causes  constriction  of 
vessels  only  when  these  are  supplied  with  constrictor  fibers  (see  page 
736),  the  conclusion  may  be  drawn  that  the  cerebral  blood  vessels  do 
contain  such  nerve  fibers.  Nevertheless,  the  local  vasomotor  control  of 
the  cerebral  blood  vessels  can  not  have  the  significance  in  connection 
with  changes  in  blood  supply  that  it  has  for  other  vascular  areas  (Hill 
and  Macleod20)-  No  doubt  nerve  fibers  are  present  in  the  cerebral 
blood  vessels,  and  presumably  under  certain  conditions  they  are  capable 
of  causing  the  blood  vessels  to  undergo  alterations  in  caliber,  but  it  is 
impossible  to  see  of  what  real  value  this  can  be  under  normal  conditions. 


PECULIARITIES   OP    BLOOD   SUPPLY    IX    CERTAIN    VISCERA  253 

Intracranial  Pressure 

One  word  more  with  regard  to  what  is  known  as  intracranial  pressure, 
that  is,  the  pressure  in  the  space  between  the  skull  and  the  brain. 
Under  ordinary  conditions  it  must  be  equal  to  that  in  the  cerebral  capil- 
laries, and  may  be  measured  by  connecting  a  sensitive  manometer  with 
a  tube  screwed  into  the  cranium* as  described  above.  It  has  been  found 
to  vary  from  0  mm.  Hg  in  a  man  standing  erect  to  50-GO  mm.  Kg  in  a 
dog  poisoned  by  strychnine.  It  becomes  increased,  not  only  by  com- 
pression of  the  veins  of  the  neck  and  by  an  increase  in  general  arterial 
pressure,  but  also  in  pathologic  conditions,  such  as  hydrocephalus.  A 
new  growth  in  the  brain,  if  it  occupies  more  space  than  the  tissue  which 
is  destroyed,  exerts  pressure  on  all  parts  of  that  region  of  the  cranial 
cavity,  but  this  pressure  may  not  be  transmitted  equally  throughout 
the  cranial  contents,  for  the  falciform  ligaments  and  the  tentorium  sup- 
port a  part  of  it,  thus  directing  the  spread  of  pressure  along  certain 
pathways.  The  structures  at  the  base  of  the  brain,  the  optic  nerves, 
the  veins  of  Galen  and  the  Sylvian  aqueduct  are  most  affected  in  this 
way.  If  the  pressure  is  rapidly  applied,  however,  it  may  rise  through- 
out the  cranial  contents.  In  such  cases  the  pressure  is,  of  course,  cir- 
culatory in  origin,  since  immediately  after  death  from  cerebral  tumor 
the  intracranial  pressure  is  not  found  to  be  raised. 

The  major  symptoms  of  cerebral  compression  are  no  doubt  due  to 
anemia  of  the  medulla  oblongata,  which  may  be  the  result  either  of 
pressure  applied  locally  in  the  bulbar  region,  where  the  presence  of  a 
very  small  foreign  body  or  only  trivial  tumor  formation  is  sufficient  to 
destroy  life,  or  of  pressure  transmitted  from  the  cerebral  cavity,  in 
which  ease,  on  account  of  the  support  offered  by  the  tentorium,  a  much 
larger  growth  is  required  to  affect  the  medulla.  Internal  hydrocephalus 
produced  by  blocking  of  the  aqueduct  of  Sylvius  and  the  veins  of  Galen 
causes  the  greatest  rise  in  intracranial  tension,  and  may  affect  the  me- 
dulla, because  the  brain  is  driven  downwards  so  as  to  pinch  the  bulb 
against  the  occipital  bone.  It  must  be  emphasized  that  it  is  not  the 
pressure  per  se  that  causes  the  symptoms,  but  the  attendant  anemia, 
the  symptoms  of  acute  cerebral  anemia  and  of  compression  being  iden- 
tical (Leonard  Hill19).  To  relieve  the  compression,  trephining  is  the 
common  practice.  The  trephine  hole  should  be  as  large  and  as  near 
to  the  source  of  compression  (tumor,  etc.)  as  possible. 

CIRCULATION  THROUGH  THE  LUNGS 

The  pulmonary  or  lesser  circulation,  as  it  is  called,  is  quite  different 
from  the  systemic  circulation.     In  the  first  place,  because  the  pressure 


254  THE    CIRCULATION    OF    THE    BLOOD 

in  the  pulmonary  arteries  does  not  amount  to  more  than  about  20  mm. 
Hg,  or  about  one-sixth  of  that  of  the  systemic  arteries,  the  peripheral 
resistance  in  the  blood  vessels  of  the  lungs  is  much  less  than  that  of 
the  body  in  general.  This  lower  resistance  is  owing  partly  to  the  large 
diameter  of  the  arterioles  and  the  small  amount  of  muscular  fibers  in 
their  walls,  and  partly  to  the  fact  that  the  capillaries  are  held  con- 
stantly in  a  somewhat  dilated  condition  on  account  of  the  subatmos- 
pheric  pressure  in  the  thorax  (see  page  306). 

Another  peculiarity  of  the  pulmonary  circulation  is  that  the  caliber 
of  the  vessels  is  to  a  very  large  extent  dependent  upon  the  changes 
that  occur  in  the  intrathoracic  pressure  with  each  inspiration  and  ex- 
piration. They  become  dilated  on  inspiration  and  contracted  on  ex- 
piration. The  extent  to  which  these  respiratory  changes  affect  the 
amount  of  blood  contained  in  the  lungs,  is  very  considerable.  At  the 
height  of  inspiration  it  is  computed  that  a  little  more  than  eight  per 
cent  of  the  whole  blood  in  the  body  is  contained  in  the  lungs,  whereas 
on  expiration  it  diminishes  to  between  five  and  seven  per  cent. 

A  third  peculiarity  is  that  the  pulmonic  blood  vessels  are  not  sup- 
plied with  vasomotor  nerve  fibers — at  least  with  such  as  can  readily  be 
demonstrated.  It  is  said  that,  when  the  pulmonary  vessels  are  per- 
fused and  the  outflow  measured,  a  diminution  in  the  latter  is  found  to 
occur  when  epinephrine  is  added  to  the  injection  fluid — a  result  which 
is,  however,  denied  by  certain  investigators.  Changes  in  the  bloodflow 
have  not  been  observed  to  occur  when  the  vagus  or  sympathetic  nerve 
fibers  running  to  the  lungs  are  stimulated.  In  short,  the  conclusion 
which  we  must  draAV  is  much  the  same  as  that  for  the  blood  vessels 
of  the  brain — namely,  that  although,  as  a  result  of  the  epinephrine  ex- 
periment, we  must  admit  that  a  vasomotor  supply  may  possibly  be 
present,  yet  it  is  one  which  can  be  of  no  significance  under  normal 
conditions. 

When  there  is  obstruction  to  the  outflow  of  blood  from  the  left  ven- 
tricle, as,  for  example,  in  cases  of  high  aortic  pressure,  the  blood  is  not 
entirely  discharged  with  each  beat  of  the  left  ventricle,  and  therefore 
dams  back  through  the  left  auricle  into  the  lungs.  On  account  of  the 
marked  distensibility  of  the  pulmonary  capillaries,  a  large  amount  of 
this  blood  may  collect  there  and  thus  make  the  lungs  serve  as  a  kind  of 
reservoir  of  the  heart.  When  the  capacity  of  this  reservoir  has,  how- 
ever, been  overstepped,  an  increased  peripheral  resistance  will  come  to 
be  offered  to  the  movement  of  blood  in  the  pulmonary  arteries,  the 
pressure  in  which  will  consequently  rise  and  sooner  or  later  interfere 
with  the  discharge  from  the  right  ventricle,  causing  as  a  result  a  stag- 
nation of  blood  in  the  systemic  veins,  and  a  consequent  increase  in  vol- 


PECULIARITIES   OF    BLOOD   SUPPLY    IN'    CERTAIN    VISCERA  255 

nine  of  such  viscera  as  the  liver  and  kidneys.  The  same  changes  will 
obviously  also  supervene  when  there  is  regurgitation  of  blood  from  the 
left  ventricle  to  the  left  auricle,  as  in  cases  of  mitral  insufficiency. 

CIRCULATION  THROUGH  THE  LIVER 

The  liver  is  the  only  gland  in  the  body  receiving  both  venous  and 
arterial  blood,  the  former  being  supplied  to  it  at  a  very  low  pressure 
by  way  of  the  capacious  portal  vein,  and  the  latter  at  very  high  pressure 
by  the  strikingly  narrow  hepatic  artery.  Except  for  the  relatively 
small  amount  of  blood  which  is  supplied  to  the  walls  of  the  blood  vessels 
and  the  biliary  duets,  none  of  the  hepatic  artery  blood  mixes  with  that  of 
the  portal  vein  until  the  vessels  enter  the  hepatic  lobules.  Beyond  this 
point  the  two  blood  streams  mix  and  the  combined  stream  is  drained 
away  by  the  sublobular  and  hepatic  veins. 

Methods   of  Investigation 

To  study  the  relative  importance  of  these  two  sources  of  blood  sup- 
ply, and  also  to  investigate  the  manner  in  which  the  latter  is  controlled, 
the  most  satisfactory  method  has  consisted  in  measurements  of  changes 
in  volume  flow  rather  than  in  those  of  changes  in  pressure.  The  vol- 
ume-flow measurement  has  been  made  either  by  connecting  stromuhrs 
(page  207)  to  the  hepatic  artery  or  portal  vein,  or  by  measuring  the  out- 
flow of  blood  from  the  hepatic  vein  into  the  vena  cava,  first  with  both 
inflow  vessels  intact,  and  then  with  one  of  them  ligated.  An  objec- 
tion to  the  first  (the  stromuhr)  method  is  the  possible  interference  with 
bloodflow  or  blood  pressure  produced  by  inserting  the  stromuhr  into 
the  entering  vessels,  and  also  the  fact  that  simultaneous  measurement 
of  the  flow  in  both  vessels  can  not  be  made  satisfactorily. 

To  measure  the  outflow  from  the  hepatic  veins,  the  aorta  is  ligated 
below  the  celiac  axis  and  a  wide  cannula  is  inserted  into  the  central 
end  of  the  vena  cava  below  the  level  of  the  liver,  a  loose  thread  being 
placed  around  this  vessel  just  above  the  diaphragm.  By  pulling  on  this 
thread  the  vena  cava  becomes  obliterated,  and  the  blood  from  the 
hepatic  veins  is  therefore  diverted  into  the  cannula,  through  which  it 
flows  into  one  end  of  a  vessel  shaped  somewhat  like  a  sputum  cup  (the 
receiver),  the  other  end  being  connected  by  tubing  with  a  piston  re- 
corder, from  the  movement  of  which  the  volume  of  blood  flowing  into 
the  receiver  can  readily  be  computed.  To  measure  the  flow  of  blood, 
a  clip  on  the  tube  of  the  receiver  is  removed  at  the  same  moment  that 
the  thread  around  the  vena  cava  above  the  diaphragm  is  tightened, 
and  when  the  receiver  has  filled  with  blood,  this  thread  is  again  loosened 


256  THE    CIRCULATION   OF    THE   BLOOD 

and  the  receiver  tilted  up  so  that  the  blood  flows  at  low  pressure  back 
into  the  circulation.  The  receiver  being  of  known  capacity,  the  length 
of  time  it  takes  the  blood  to  fill  it  as  determined  by  the  piston  recorder, 
furnishes  us  with  the  necessary  data  from  which  to  calculate  the  rate 
of  flow.  The  receiver  is  chosen  of  such  a  size  that  it  takes  only  a  few 
seconds  to  fill,  the  diversion  of  blood  into  it  not  causing  any  material 
fall  in  arterial  pressure.     The  observations  are  repeated  frequently. 

Results. — By  the  use  of  these  methods  it  has  been  found  that  the  total 
mass  movement  of  blood  to  the  liver  of  the  dog  varies  between  1.46  and 
2.40  c.c.  per  second  for  100  grams  of  liver.  Considerable  changes  may 
occur  in  the  arterial  pressure  without  affecting  the  liver  flow.  AVhen 
the  hepatic  artery  is  occluded,  the  flow  diminishes  by  about  30  per 
cent,  or  conversely,  when  the  portal  vein  is  obstructed  but  the  hepatic 
artery  left  intact,  by  about  60  per  cent,  indicating  that  about  one-third 
of  the  total  bloodflow  through  the  liver  is  contributed  by  the  hepatic 
artery  and  two-thirds  by  the  portal  vein.  Some  blood,  however,  gains 
the  liver  through  anastomotic  channels  between  it  and  the  diaphrag- 
matic veins. 

The  relative  supply  by  the  two  vessels  is  subject  to  various  condi- 
tions. That  through  the  hepatic  artery,  for  example,  may  be  very  con- 
siderably altered  on  account  of  vasoconstriction  in  this  vessel,  for  its 
walls  can  easily  be  shown  to  be  liberally  supplied  with  vasoconstrictor 
fibers  carried  by  the  hepatic  plexus.  This  can  be  demonstrated  by 
the  rise  in  blood  pressure  which  occurs  in  a  branch  of  the  hepatic  artery 
during  stimulation  of  the  plexus.  On  the  other  hand,  alterations  in  the 
bloodflow  in  the  portal  vein  can  not  be  brought  about  by  active  con- 
striction or  dilatation  of  the  intrahepatic  branches  of  this  vessel,  no 
active  vasomotor  fibers  having  been  demonstrated  by  stimulation  of 
the  hepatic  nerves,  although,  as  in  the  case  of  the  brain  and  lung  blood 
vessels,  a  certain  amount  of  constriction  may  occur  under  the  influence 
of  epinephrine. 

The  bloodflow  through  the  portal  vein  is  dependent  on  changes  oc- 
curring at  either  end  of  the  distribution  of  the  vessel,  that  is,  changes 
occurring  in  the  liver  itself  or  in  the  intestine.  Of  these  factors  the  lat- 
ter is  no  doubt  the  more  important,  an  increase  not  only  in  portal  blood 
pressure  but  also  in  portal  bloodflow  being  readily  produced  by  dila- 
tation of  the  splanchnic  blood  vessels;  for  example,  as  the  result  of  sec- 
tion of  the  splanchnic  nerve.  Alterations  in  portal  bloodflow  brought 
about  by  changes  in  the  caliber  of  the  vessels  in  the  liver  itself  are 
partly  dependent  upon  changes  in  the  branches  of  the  hepatic  artery. 
Let  us  consider  briefly  how  this  may  be  brought  about.  At  the  point 
where  the  portal  and  hepatic  arteries  come  together — that  is,  at  the  in- 


PECULIARITIES   OF    BLOOD   SUPPLY    IN    CERTAIN    VISCERA  -">7 

trahepatic  capillaries-  the  pressure  of  the  blood  in  them  musl  become 
equal,  which  means  thai  in  its  course  through  the  interlobular  connec- 
tive (issue,  the  branches  of  the  hepatic  artery  musl  offer  much  resistance 
to  the  blood  flowing  through  them.    This  frictional  resistance  resides  in 

the  hepatic  arterioles,  and  since  these  are  richly  supplied  with  constric- 
tor nerves,  great  variation  in  hepatic  inflow  becomes  possible.  These 
changes  will  affect  the  degree  of  tension  of  the  interlobular  connective 
tissue  in  which  the  arterioles  lie.  In  this  tissue,  however,  also  lie  the 
thin-walled  branches  of  the  portal  vein.  When  therefore  the  tension 
of  this  tissue  becomes  greater,  as  a  result,  for  example,  of  vasodilatation 
in  the  hepatic  artery,  the  portal  vein  radicles  will  become  compressed 
and  the  bloodflow  along  them  impeded.  Conversely,  when  vasocon- 
striction occurs  in  the  hepatic  arteries,  the  congestion  of  the  connective 
tissue  becomes  diminished,  the  veins  dilate,  and  the  blood  flows  through 
them  more  readily  (Macleod  and  R.  G.  Pearce21).  Experimental  evi- 
dence in  support  of  the  above  view  is  furnished  by  observing  the  out- 
flow of  blood  from  the  liver  before  and  during  stimulation  of  the  he- 
patic plexus.  The  first  effect  is  an  increase  in  the  outflow,  which  very 
soon  returns  to  its  original  amount,  even  though  the  stimulation  of  the 
plexus  is  kept  up  during  the  experiment.  This  return  to  the  normal 
flow  must  indicate  either  that  the  constriction  of  the  hepatic  artery  has 
not  been  maintained,  or  that  it  has  been  maintained  but  is  accompanied 
by  a  compensatory  increase  in  the  flow  through  the  portal  vein.  As 
a  matter  of  fact,  we  know  that  the  hepatic  artery  remains  constricted 
as  long  as  the  hepatic  plexus  is  stimulated,  indicating  that  the  conges- 
tion of  the  connective  tissue  in  which  the  venules  lie  has  become  reduced 
to  such  an  extent,  as  a  result  of  the  constriction,  that  these  open  up  and 
permit  the  blood  to  flow  through  them  more  readily.  The  initial  in- 
crease in  outflow  immediately  following  upon  stimulation  of  the  hepatic 
plexus,  is  no  doubt  caused  by  the  squeezing  out  of  the  blood  already  in 
the  hepatic  vessels,  and  it  is  a  result  which  is  often  observed  in  other 
organs  during  stimulation  of  vasoconstrictor  nerve  fibers. 

THE  CORONARY  CIRCULATION 

We  have  already  studied  the  effect  produced  on  the  heartbeat  by  in- 
terfering with  the  flow  of  blood  in  the  coronary  vessels,  and  it  remains 
for  us  to  study:  (1)  peculiarities  in  the  bloodflow  through  them,  and 
(2)  whether  this  bloodflow  can  be  altered  by  dilatation  or  constriction 
of  the  vessels  brought  about  through  nerves.  With  regard  to  the  pecu- 
liarities of  bloodflow,  it  may  be  stated  that  there  is  said  to  be  two  periods 
in  each  cardiac  cycle  during  which  an  increase  takes  place  in  the  mass 


258  THE    CIRCULATION   OP    THE   BLOOD 

movement  of  blood  in  the  coronary  vessels — namely,  at  the  beginning 
of  systole,  and  again  at  the  beginning  of  diastole.  Nevertheless  the 
pressure  pulse  has  the  same  contour  in  the  coronary  as  in  the  systemic 
circulation.  (W.  T.  Porter.22)  During  systole  the  intramural  branches 
of  the  coronary  artery  are  compressed  and  the  blood  pressed  out  of 
them.  This  emptying  of  the  vessels  favors  the  flow  of  blood  through 
the  heart  walls. 

Regarding  the  presence  of  coronary  vasomotor  nerves,  there  is  at  pres- 
ent a  certain  amount  of  doubt.  When  strips  of  the  coronary  artery  are 
suspended  in  a  solution  of  epinephrine,  they  undergo  relaxation  instead 
of  contraction.  On  the  assumption  that  the  action  of  epinephrine  on 
blood  vessels  is  the  same  as  that  of  stimulation  of  the  vasoconstrictor 
fibers,  this  result  has  been  taken  as  evidence  of  the  absence  of  such 
fibers  and  the  possible  presence  of  vasodilator  fibers.  A  somewhat 
similar  type  of  experiment  has  been  performed  by  injecting  epineph- 
rine into  the  fluid  used  to  perfuse  the  excised  mammalian  heart, 
with  the  result  that,  when  such  injections  are  made  into  a  heart  that 
is  not  beating,  evidence  of  vasoconstriction  is  obtained,  whereas  when 
injected  into  a  beating  heart,  dilatation  occurs.  This  latter  result 
may,  however,  be  owing  to  the  action  of  the  epinephrine  in  stimulating 
the  cardiac  contractions.  Other  observers,  however,  deny  that  the  in- 
jection of  epinephrine  into  the  coronary  circulation  has  any  influence 
upon  the  outflow  of  the  perfusion  fluid.  Taking  the  result  of  these 
observations  as  a  whole,  we  may  at  least  conclude  that  epinephrine 
does  not  produce  the  same  marked  vasoconstriction  that  it  produces  in 
other  blood  vessels — a  fact,  which,  as  already  stated,  may  be  taken 
advantage  of  in  bringing  about  the  rise  in  coronary  pressure  that  is 
necessary  for  successful  resuscitation  of  the  heart. 

Attempts  to  demonstrate  the  presence  of  vasomotor  fibers  by  electrical 
stimulation  of  the  vagus  or  sympathetic  nerve  have  yielded  results  which 
are  quite  inconclusive,  although  some  observers  assert  that  the  vagus 
nerve  carries  vasoconstrictor  fibers  to  the  coronary  vessels,  and  that 
the  sympathetic  carries  vasodilator. 


CHAPTER  XXIX 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGIC 

METHODS* 

In  the  following  chapters  a  brief  account  will  be  offered  of  the  clinical 
use  of  the  electrocardiogram,  of  polysphygmograms,  and  of  bloodnow 
measurements.  This  is  done  to  show  how  physiologic  technic  is  being 
employed  for  the  accurate  investigation  of  cardiovascular  disease. 

ELECTROCARDIOGRAMS 

To  observe  the  electrical  change  produced  by  the  spread  of  the  excita- 
tion wave  over  the  heart  from  auricles  to  ventricles,  it  is  not  necessary 
to  place  the  electrodes  directly  on  the  heart,  but,  as  already  hinted,  we 
may  follow  the  electrical  change  by  leadiitg  off  from  electrodes  applied 
to  the  surface  of  the  body.  From  such  electrocardiographic  tracings 
extremely  important  facts  concerning  the  propagation  of  the  heartbeat 
may  be  ascertained.  In  order  to  make  an  observation  the  hands  and  the 
left  foot  are  each  placed  in  a  solution  of  sodium  chloride  contained  in 
porous  jars,  immersed  in  larger  vessels  containing  a  saturated  solution  of 
ZnS04  and  zinc  terminals. t  An  arrangement  like  that  in  Fig.  81  may  also 
be  used.  By  manipulation  of  suitable  keys  the  extremities1  may  then  be 
connected  with  the  electrocardiograph  in  the  following  manner:  Lead  1, 
right  arm  and  left  arm;  lead  2,  right  arm  and  left  leg;  lead  3,  left  arm 
and  left  leg.  Through  lead  1,  the  current  acting  on  the  galvanometer  will 
be  that  produced  more  especially  at  the  base  of  the  heart.  Through  lead 
2,  the  current  will  pass  through  the  long  axis  of  the  heart,  and  through 
lead  3,  it  will  pass  mainly  along  its  left  border. 

When  any  pair  of  leads  is  connected  with  the  galvanometer,  it  is  ob- 
served that  the  string  is  deflected  to  one  side  owing  to'  electrical  cur- 
rents arising  from  the  skin.  Before  taking  a  record  of  the  cardiac 
movements  of  the  string,  it  is  necessary  to  compensate  for  this  skin  cur- 
rent by  introducing  into  the  circuit  in  the  opposite  direction  the  re- 


*A  certain  amount  of  repetition  of  matter  previously  discussed  has  been  found  advisable  in  these 
chapters  for  which   the  indulgence  of  the  reader  is   requested. 

tit  is  really  unnecessary  to  use  the  so-called  nonpolarizable  electrodes.  Glass  vessels  containing 
20  per  cent   NaCl   solution   with   the   zinc   plates   dipping   into   them   are   quite   satisfactory. 

259 


260 


THE   CIRCULATION   OF   TIIK    BLOOD 


quired  amount  of  current,  called  the  compensating  current,  to  bring  the 
strong  shadow  hack  to  the  zero  or  midposition.  In  order  that  the  rec- 
ord obtained  may  he  quantitative  in  character,  it  is  further  necessary 
that  the  movement  of  the  string  he  standardized.  This  is  done  by  as- 
certaining to  what  extent  the  string  moves  when  a  current  of  known 
voltage  is  sent  through  it  and  by  altering  the  tension  of  the  string  so  that 
one  millivolt  of  current  causes  an  exclusion  of  one  centimeter  of  the 
string  shadow  on  the  photographic  plate.     It  would  take  us  beyond  the 


Eig.    81. — Electrocardiographic   apparatus   as   made   by    the    Cambridge    Scientific    Materials    Co.      Con- 
tact electrodes  are  shown,  but  the   immersion  electrodes  described   in  the  context  are  preferable. 


confines  of  this  volume  to  go  in  any  greater  detail  into  the  technic  in- 
volved in  taking  electrocardiograms,  but  it  may  be  said  that  this  is  by 
no  means  difficult,  provided  the  instructions  which  are  supplied  with 
the  instrument  are  carefully  followed.  In  practice  the  taking  of  elec- 
trocardiograms is  indeed  quite  a  simple  matter,  and  the  extremely  im- 
portant information  which  they  give  us  concerning  the  mechanism  of 
the  heartbeat  and  the  evidence  of  myocardial  disease  should  make  their 
employment  a  universal  practice  in  all  cardiac  clinics.  Some  of  these 
clinical  applications  arc  described  elsewhere  (page  266). 


ELECTROCARDIOGRAMS 


261 


What  particularly  interests  us  here  is  the  contour  of  the  electrocardio- 
gram in  n  normal  person  (Fig.  82).  It  will  be  observed  thai  there  are 
three  waves  above  the  Line  of  zero  potential  and  two  waves  below  it. 
They   have   been   lettered    from   before  backward,    P,  <,),   R,   S,   and  T, 

and  in  all  such  records  when  correctly  obtained,  the  waves  above  the 
line  of  zero  potential  indicate  that  the  base  of  the  heart  is  negative  to 
the  apex.  The  exact  cause  of  each  wave  has  been  ascertained  by  taking 
simultaneously  with  the  electrocardiogram  a  record  of  the  mechanical 
changes  occurring  in  the  heart  during  each  cardiac  eycle.     Such  records 


Fig.    82. — Normal    electrocardiogram.      Leads    1,    2,    3.      Note    that   the    height   of    the   R   deflection    in 
lead    3    equals   the    difference    between    the    height    of   Rx    and    R2. 


have  been  secured  by  taking  intracardiac  pressure  curves  with  the  results 
as  shown  in  Fig.  83.  The  top  curve  represents  auricular  and  the  second 
one  ventricular  pressure,  Avhereas  the  lowest  is  an  electrocardiogram. 
It  will  be  observed:  (1)  that  the  P-wave  occurs  just  antecedent  to  con- 
traction of  the  auricles;  (2)  that  the  small  positive  wave,  Q,  which  is  ab- 
sent in  these  tracings,  must  occur  just  before  the  beginning  of  the  con- 
traction of  the  ventricles;  (3)  that  the  negative  wave,  R,  occurs  just  be- 
fore and  during  the  early  part  of  ventricular  systole — that  is,  during 
the  presphygmic  period;  and  (4)  that  the  long  upward  wave,  T,  culmi- 
nates at  the  moment  the  ventricle  begins  relaxing. 


262 


THE    CIRCULATION    OP    THE    BLOOD 


Although  such  comparisons  give  us  considerable  insight  into  the  cause 
of  several  of  the  waves,  there  yet  remain  certain  peculiarities  of  the 
electrocardiogram  to  be  considered.  These  are:  (1)  the  cause  of  the 
slight  positive  wave,  Q;  (2)  the  cause  of  the  positive  wave,  S;  (3)  the 
cause  for  the  period  of  equal  potential  at  the  base  and  apex  during  ven- 
tricular systole  indicated  by  the  portion  of  the  curve  between  S  and  T ; 
(4)  the  cause  for  the  negative  wave,  T.  To  solve  these  problems  it  is 
necessary  to  compare  electrocardiograms  taken  from  the  surface  of  the 
body  with  those  from  electrodes  placed  directly  on  the  base  or  apex  of 
the  ventricle  of  the  exposed  heart. 


Fig.  83.— -Electrocardiogram  (dog)  taken  simultaneously  with  curves  from  auricle  and  ven- 
tricle. It  will  be  observed  that  wave  P  slightly  precedes  auricular  systole  and  that  wave  R  occurs 
just   before   the   presphygmic   period   starts   in    the   ventricle.      (From    Lev/is.) 


The  Ventricular  Complex 

In  view  of  the  nature  of  the  electric  change  which  occurs  in  a  strip 
of  denervated  muscle  when  a  wave  of  contraction  passes  along  it  (page 
188),  the  simplest  interpretation  of  the  ventricular  part  of  the  above 
curve  is  that  the  contraction  must  pass  into  the  ventricle  at  a  little  dis- 
tance from  the  base,  thus  causing  the  latter,  for  a  moment  of  time,  to  be 
positive  to  the  rest  of  the  ventricle,  and  accounting  for  the  slight  down- 
ward wave,  Q.  Immediately  after  this  the  base  of  the  ventricle  becomes 
negative  to  the  apex,  giving  us  the  marked  upward  wave,  R,  which 
however  lasts  for  but  a  short  period  of  time,  being  followed  by  an  inter- 
val during  which  the  base  and  apex  are  of  the  same  electrical  potential 
(horizontal  part  of  wave  between  R  and  T).  Finally  the  base  again  be- 
comes negative  to  the  apex,  thus  accounting  for  the  smaller  upward 


ELECTROCARDIOGRAMS  263 

wave,  T.  The  cause  of  the  occasionally  observed  downward  wave,  S, 
following  R,  is  obscure. 

The  most  significant  fact  in  the  electrocardiogram  is  therefore  that 
the  base  is  negative  to  the  apex  at  the  beginning  (R-wave)  and  again  at 
the  end  (T-ivave)  of  the  ventricular  contraction.  How  may  this  be  ex- 
plained? When  electrocardiograms  are  taken  through  electrodes  placed 
directly  on  the  base  and  apex  of  the  ventricle  of  the  exposed  heart,  it 
has  been  found  that  the  contour  of  the  electrocardiogram  is  like  that 
which  is  obtained  from  a  strip  of  muscle  when  a  wave  of  contraction 
passes  along  it:  it  is  diphasic  in  character  (page  188),  a  result  which 
may  be  interpreted  as  indicating  that  the  wave  of  contraction  starts  at 
the  base  and  ends  at  the  apex.  This  rules  out  the  explanation,  at  one 
time  suggested  for  the  T-wave,  that  the  wave  starts  at  the  base,  then 
proceeds  to  the  apex,  and  finally  ends  at  the  base,  following  the  disposi- 
tion of  the  muscular  fibers  of  the  ventricle  in  a  folded  or  loop  form, 
with  the  bend  of  the  loop  at  the  apex  and  the  free  ends  at  the  base.  Al- 
though the  explanation  seemed  at  first  to  conform  with  the  embryo- 
logic  fact  that  the  heart  is  developed  from  a  folded  tube,  it  can  not  hold, 
as  has  been  shown  by  observing  the  course  of  the  excitation  wave  se- 
cured through  electrodes  placed  at  various  points  on  the  surface  of  the 
exposed  ventricle  (page  194). 

The  explanation  which  is  accepted  by  the  majority  of  observers  at  the 
present  time  is  to  the  effect  that  the  T-wave  is  caused  by  the  longer  con- 
tinuance of  the  electric  change  at  the  base  of  the  ventricle  than  at  the 
apex.  To  test  this  hypothesis  the  crucial  experiment  would  evidently 
be  to  see  whether  a  T-wave  could  be  induced  in  an  electrocardiogram, 
such  as  that  of  the  frog  ventricle,  in  which  no  T-wave  exists,  by  hurry- 
ing up  the  contraction  process  at  the  apex  without  affecting  it  at  the 
base.  This  can  be  done  by  local  warming  of  the  apex,  or  by  applying 
the  ventricular  electrode  at  varying  parts  of  the  ventricle  in  an  excised 
heart  beating  in  Ringer's  solution  of  relatively  high  H-ion  concentra- 
tion. Mines  showed  that  under  these  conditions  a  typical  T-wave  ap- 
pears in  the  electrocardiogram,  as  shoAvn  in  Fig.  84.* 

The  existence  of  the  small  Q-wave,  indicating  that  the  contraction 
does  not  really  start  from  the  base,  conforms  with  the  observation  that 
the  Purkinje  system  of  fibers  ends  about  the  papillary  muscles,  which 
therefore  would  be  the  first  to  contract,  and  with  the  observations  of 
Lewis,  already  alluded  to  above,  on  the  appearance  of  the  negative  vari- 
ation on  the  surface  of  the  exposed  heart. 

The  most  important  clinical  application  of  the   electrocardiogram  is 


*This  tracing  was   found   among  those   left   by   Professor   Mines   of   McGill   University,    and   for 
permission    to    use    it    the    author    is    indebted    to    the    authorities    of    that    institution. 


264 


THE    CBRCULATION    OF    THE    BLOOD 


e> 


«W 


\te£&a*viadL 


B. — Apex    cooled 


C. — Apex   warmed 

Fig.  84. — Records  of  electrocardiogram  and  movement  of  ventricle  of  frog  showing  that  when 
the  apex  is  warmed  a  typical  T-wave  appears  in  place  of  a  wave  in  the  opposite  direction  appear- 
ing  when   the  apex   is  cooled.      (From   Mines.) 


ELECTROCARDIOGRAMS  265 

undoubtedly  in  connection  with  the  determination  of  the  rah  of  trans- 
mission of  the  excitation  wave  Erom  auricle  l<>  ventricle;  thus,  the  l'-li 
interval,  as  it   is  called,  indicates  the   time  taken    Eor  the   impulse  to 

travel  from  the  sinoanrieiilar  to  the  aiifieiilovenl  ricular  node  and  bundle. 
In  delayed  transmission  tins  interval  becomes  abnormally  long.  Obvi- 
ously also  conditions  of  heart-block,  of  auricular  fibrillation,  or  of  auric- 
ular flutter  will  be  immediately  revealed  by  the  electrocardiogram.  The 
interpretation  of  abnormalities  in  the  contour  of  the  ventricular  portion 
of  the  curve  is,  however,  not  so  easy  a  matter,  and  should  never  be 
undertaken  unless  curves  from  the  three  leads  have  been  secured,  for  it 
Avill  be  found  that  the  corresponding  electrocardiograms  differ  from 
one  another  in  detail;  for  example,  the  R-wave  is  usually  most  prominent 
in  lead  2,  although  sometimes  it  is  more  prominent  in  lead  3.  T  is  always 
upright  in  normal  individuals  in  curves  taken  from  lead  2,  but  it  is  not 
infrequently  inverted  in  those  of  lead  3,  and  may  show  partial  inversion 
in  those  from  lead  1.  The  Q-R-S  group  is  often  of  peculiar  contour  in 
curves  from  lead  3.  These  variations  are  possibly  dependent  upon  the 
relative  preponderance  of  the  musculature  in  the  left  and  right  ven- 
tricles, for  it  is  evident  that  the  amount  of  muscle  included  in  the  path- 
way between  the  two  leads  will  vary. 


CHAPTER  XXX 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGIC 
METHODS  (Cont'd) 

CLINICAL  APPLICATIONS  OF  ELECTROCARDIOGRAPHY 

The  Electrocardiogram  in  the  More  Usual  Forms  of  Cardiac 

Irregularities 

By  R.  W.  Scott 

The  principle  of  the  application  of  the  string  galvanometer  to  the 
study  of  cardiac  irregularities  has  been  indicated.  It  is  our  object  here 
to  outline  some  of  the  more  common  forms  of  irregular  heart  action, 
with  a  brief  description  of  the  abnormalities  in  the  electrocardiogram 
resulting  therefrom.  For  the  sake  of  comparison  a  normal  electrocar- 
diogram is  shown  in  Fig.  82.  The  cause  and  relationship  of  the  various 
deflections  have  been  explained  (see  page  262). 

Sinus  Arrhythmia. — This  irregularity  is  seen  commonly  in  children 
and  young  adults,  and  is  without  pathologic  significance.  The  electro- 
cardiogram presents  the  normal  deflections  and  shows  by  the  varying 
spaces  between  the  P  deflections  that  the  cardiac  impulse  has  been  gen- 
erated at  slightly  irregular  intervals. 

Sinus  Bradycardia. — The  electrocardiogram  in  a  simple  case  of  sinus 
bradycardia  is  usually  normal,  except  that  the  deflections  occur  at  an 
unusually  slow  rate  (Fig.  85).  This  indicates  that  the  cardiac  impulse, 
is  built  up  at  a  sIoav  rate,  but  when  generated  it  evokes  a  normal  auric- 
ular and  ventricular  contraction. 

The  Extrasystole. — The  extrasystole  may  be  either  auricular  or  ven- 
tricular in  origin.  Occasionally  a  rare  type  is  seen  in  which  the  im- 
pulse arises  in  the  junctional  tissues  between  the  auricle  and  ventricle. 
When  the  focus  of  impulse  production  is  at  or  near  the  sinoauricular 
node,  the  resulting  electrocardiogram  complexes  are  practically  normal. 
If,  however,  the  seat  of  impulse  formation  is  removed  from  the  S-A 
node,  the  P  deflection  may  be  distorted  or  actually  inverted,  followed 
by  a  normal  Q-R-S-T  complex  (Fig.  86). 

In  the  case  of  ventricular  extrasystole,  the  cardiac  impulse  originates 
in  either  the  right  or  the  left  ventricle.     This  abnormal  site,  together 

26G 


CLINICAL   APPLICATIONS   OF    ELECTROCARDIOGRAPHY 

^  i  ~       "  ~  *     ■ '"  -.  :;:.: 


267 


mstfmf/\m 


*  i 


Fig.    85. — Sinus   bradycardia.      Kate    32    per    minute.      Note    the    normal    appearance    of    the    electro- 
cardiogram.     P-R   interval  =  .17   seconds. 


Fig.    86. — Auricular    extrasystole.       Two    auricular    cxtrasystoles    following    two     normal     complexes. 
Note    the    ectopic   origin   of   the   extrasystoles   indicated   by    the    inversion   of    P. 


Fig.    87. — Ventricular    extrasystoles    arising   in   the    right   ventricle. 


Fig.    88. — Ventricular    extrasystole    arising    in    the    left   ventricle. 


268 


THE    CIRCULATION    OF    THE    BLOOD 


with  the  path  which  the  impulse  takes,  produces  a  much  greater  differ- 
ence of  electric  potential  than  .is  seen  in  the  normal  electrocardiogram. 
When  the  impulse  arises  in  the  right  ventricle  near  the  base,  the  prin- 


Fig.    89. — Paroxysmal   tachycardia.      Auricular   origin.      Note   that   the   P   deflection    falls    back   on    T. 

Rate    200   per   minute. 

cipal  R  deflection  is  upwards  in  both  leads  1  and  2.  Arising  near  the 
apex,  the  principal  R  deflection  is  up  in  lead  1  and  down  in  lead  2.  Two 
extrasystoles  both  arising  in  the  right  ventricle  are  shown  in  Fig.  87. 


H 

1 

! 

7? 

-D 

*A» 

i 

i- -   - 

. 

! 

2. 

i 

1 

, 

njmnJjK^^. 

^_  _            j               j^ 

— 

3 

^p|| 

I                          } 

'kj6m 

. .  «. 

Fig.  90. — Auricular  fibrillation.  Leads  1,  2,  3.  Note  the  coarse  fibrillation  waves  between  the 
R  peaks,  and  the  absence  of  any  B  deflections  in  relation  to  R.  Also  the  unequal  spacing  of  the  R 
deflections. 

In  the  case  of  the  left  ventricle,  a  basal  impulse  gives  a  downward 
principal  deflection  in  lead  1  and  up  in  lead  2.  When  the  aberrant  fo- 
cus is  located  near  the  apex  of  the  left  ventricle,  the  principal  deflec- 


CLINICAL    APPLICATIONS   <>K    ELECTROCARDIOGRAPHY  200 

tion  is  down  in  both  leads  1  and  2.  Any  one  or  Beveral  of  the  general 
types  iif  extrasystole  may  occur  in  the  same  patient.  Fig.  88  shows 
an  extrasystole  originating  from  the  lefl   ventricle. 

Paroxysmal  Tachycardia.-  -Electrocardiographic  records  taken  in  the 
interval  between  the  paroxysms  may  appear  normal.  During  the  tachy- 
cardia  the  records  normally  show-  only  two  deflections,  R  and  a  combina- 
tion of  T  and  the  succeeding  P  (Fig.  89).  If  the  paroxysm  is  of  auric- 
ular origin,  the  P  deflection  may  he  inverted,  indicating  that  the  new 
focus  of  impulse  production  is  Located  at  some  other  site  than  the  sino- 
aurieular  node.  Rarely  the  new  focus  may  be  in  the  ventricles.  Records 
taken  during  the  paroxysm  may  show  a  rapid  succession  of  deflections, 
simulating  isolated  ventricular  extrasystoles. 

Auricular  Fibrillation. — The  electrocardiogram  in  auricular  fibrilla- 
tion sIioavs  three  distinctive  features: 

1.  Absence  of  the  P  deflections  typical  of  auricular  contractions. 

2.  The  ventricular  complexes  (Q-R-S-T  waves)  occur  in  irregular  se- 
quence and  may  vary  in  height. 

3.  The  presence  of  small  irregular  oscillations  best  seen  between  the 
ventricular  complexes.  A  typical  tracing  of  this  condition  is  shown  in 
Fig.  90. 

The  dependence  of  the  P-wave  upon  auricular  contraction  has  been 
indicated  (page  261).  Its  absence  in  auricular  fibrillation  is  accounted 
for  by  the  fact  that  the  individual  muscle  fibers 'of  the  auricles  contract 
independently  of  one  another,  so  that  some  fibers  are  in  a  state  of  con- 
traction while  others  are  relaxed.  This  renders  impossible  a  coordinate 
contraction  of  the  auricle  as  a  whole. 

The  multiple  impulses  from  the  fibrillating  auricles  reach  the  ventri- 
cles and  evoke  a  contraction  provided  the  ventricle  is  not  already  in  a 
state  of  contraction  (refractory  period,  page  178).  These  irregular 
ventricular  responses  will  of  course  produce  unequal  spacing  of  the 
ventricular  complexes  in  the  electrocardiogram.  The  variations  in  the 
height  of  the  R  deflections  is  thought  to  be  due  to  the  distortion  caused 
by  the  superimposition  of  the  small  waves  representing  auricular  ac- 
tivity. These  small  waves  must  occur  throughout  the  whole  cardiac 
cycle,  but  are  more  or  less  masked  by  the  ventricular  complexes,  appear- 
ing as  separate  oscillations  only  during  diastole. 

Auricular  Flutter. — Auricular  flutter  was  discovered  by  the  electro- 
cardiograph, and  it  is  practically  impossible  to  make  a  diagnosis  of  this 
condition  without  the  use  of  the  string  galvanometer.  The  auricular 
deflections  are  usually  rhythmic  and  in  the  average  case  vary  in  rate 
from  200  to  350  per  minute.  The  initial  deflection  of  P  may  be-  base 
negative  or  apex  negative — up  or  down — depending  on  the  site  of  the 


270 


THE    CIRCULATION    OP    THE   BLOOD 


origin  of  the  auricular  impulse  (when  arising  from  some  other  source 
than  the  S-A  node  the  impulse  is  said  to  be  ectopic).  Usually  a  regular 
succession  of  P  deflections  can  be  traced  throughout  the  record  (Fig. 
91). 

Since  it  is  impossible  for  the  ventricle  to  respond  to  all  the  impulses 
coming  from  the  auricles,  a  condition  of  partial  heart-block  obtains 
(2:1 — 3:1 — 4:1,  etc.).  The  ventricular  complexes  will  occur  regularly 
except  when  a  3:2  rhythm  exists. 


Fig.   91. — Auricular  flutter.     Auricular  rate  300.     Ventricular  rate  80.     Note  the  inversion  of  the  P 

deflections. 

Usually  the  ventricular  complexes  are  such  as  to  indicate  that  the 
stimulus  arose  in  the  auricle  (supraventricular).  The  height  of  the 
individual  deflections  Q-R-S-T  may  vary,  depending  on  the  predominance 
of  a  right  or  left  ventricular  hypertrophy. 


\T-B  | 


Fig.    92. — Delayed    conduction.      Note    the    normal    appearance    of    the    electrocardiogram    except    for 
the   prolongation    of   the   P-R    interval,    which    measures    .23    seconds. 

Heart-block. — There  are  three  degrees  of  severity  in  heart-block:  (1) 
delayed  conduction,  (2)  partial  dissociation,  and  (3)  complete  dissocia- 
tion. 

Any  one  of  these  conditions  may  be  present  in  the  same  patient,  at 
successive  intervals. 

Delayed  Conduction. — When  the  conducting  tissues  of  the  heart  are 
so  affected  as  to  cause  an  abnormal  prolongation  of  the  P-R  interval, 
the  condition  is  called  delayed  conduction.  The  ventricles  respond  to 
each  stimulus  originating  at  the  sinus  node,  but  the  time  required  for  the 
impulse  to  pass  through  the  conducting  tissues  is  longer  than  normal. 


CLINICAL   APPLICATIONS    OF    KLF.CTRO)  'A  KDK  XiKAI'I I  V 


271 


In  a  simple  case  the  electrocardiogram  may  appear  perfectly  normal, 
but  when  the  PR  interval  is  measured  accurately,  it  will  be  found  to  be 
lengthened  beyond  the  extreme  limits  of  the  normal  (0.20  seconds)  (Fig. 
92). 

Partial  Dissociation. — In  the  typical  case  of  partial  dissociation  the 


Fig.    93. — Partial    dissociation.      Note    the    failure    of    ventricular    response    following    the    second    P, 
which    has   been   preceded    by   two    extrasystoles    (x)    of   ventricular   origin. 

ventricles  respond  to  the  impulse  coming  from  the  auricle  most  of  the 
time,  but  occasionally  fail  to  do  so,  when  the  condition  is  called  "dropped 
beat."  The  electrocardiogram  records  a  P  deflection  but  no  ventricular 
complex,  showing  that  the  auricles  have  contracted  at  their  usual  rate 
but  that  the  ventricles  failed  to  respond  to  the  stimulus  coming  from 
the  sinoauricular  node  (Fig.  93). 


I 


Fig.   94. — Complete   dissociation.     Note  that  the  P   wave  spaces   regularly  and   bears   no   definite   re- 
lation to  the  R  wave  of  the  ventricular  complex.     Auricular  rate   72.     Ventricular  rate  40. 

Complete  Dissociation. — In  a  simple  case  of  complete  dissociation 
the  auricles  beat  independently  of  the  ventricles;  hence  the  P  deflection 
of  the  electrocardiograms  bears  no  relation  to  the  ventricular  complex 
(Q-R-S-T)  (Fig.  94).  The  P  deflections  space  regularly  and  are  easily 
made  out  when  they  fall  during  diastole  of  the  ventricle.     Occasionally 


272  THE    CIRCULATION    OF    THE   BLOOD 

the  auricle  will  happen  to  contract  during  ventricular  systole,  causing  a 
distortion  of  the  ventricular  complex  by  the  superimposition  of  a  P 
deflection.  Except  when  this  occurs  the  Q-R-S-T  complex  is  the  normal 
supraventricular  type.  The  P  deflections  occur  more  frequently  than 
the  Q-R-S-T  complex,  showing  that  the  auricles  are  beating  more  often 
tl'an  the  ventricles.  The  auricular  rate  in  the  average  case  of  complete 
heart-block  is  about  72,  while  the  ventricular  rate  is  much  slower  (35 
to  40). 


CHAPTEK  XXXI 

CLINICAL  APPLICATIONS  OF  CERT  A  [N  PHYSIOLOGIC 

METHODS  (Cont'd) 

POLYSPHYGMO  GRAMS 

In  taking  polysphygmograms,  the  following  technic  is  usually  followed: 

Venous  Pulse  Tracings. — Direct  the  observed  person  to  lie  down  with 
his  head  slightly  raised  by  a  cushion  and  hent  to  the  right  side.  Place 
the  receiver  (thistle  funnel)  over  the  jugular  bulb  on  the  right  side  of 
the  neck.  This  lies  immediately  above  the  inner  end  of  the  clavicle. 
Bring  the  style  of  the  recording  tambour  to  write  with  a  minimal 
amount  of  friction  on  the  paper  or  drum.  Since  a  venous  pulse  tracing 
can  not  be  interpreted  without  a  simultaneous  tracing  from  an  artery, 
now  adjust  the  button  of  a  receiving  tambour  over  the  radial  artery  and 
adjust  the  style  of  its  recording  tambour  so  as  to  write  on  the  drum  in 
the  same  perpendicular  as  the  style  of  the  venous  tambour. 

Tracings  should  be  taken  with  the  recording  surface  at  a  moderate 
speed.  Before  disturbing  the  relative  positions  of  the  writing  points, 
allow  them  to  make  vertical  marks  (with  recording  surface  stationary) 
at  various  parts  of  the  tracings.  These  alignment  marks  permit  of  ac- 
curate comparisons  between  the  curves.  Repeat  the  above,  using  the 
carotid  instead  of  the  radial.  A  time  tracing  (%  sec.)  should  always  be 
taken  simultaneously.     The  poly sphygmo graph  is  shown  in  Fig.  95. 

To  interpret  the  venous  curve,  make  a  vertical  mark  on  the  arterial 
pulse  tracing  corresponding  to  the  beginning  of  the  pulse  upstroke.  If 
this  is  done  on  the  radial  pulse  tracing,  measure  one-tenth  of  a  second  in 
front  of  it,  and  make  a  vertical  mark  to  allow  for  the  time  lost  in  propa- 
gation of  the  pulse  from  the  heart  to  the  radial  artery. 

This  line  3  (corrected  in  case  of  radial  pulse)  corresponds  to  the  be- 
ginning of  the  sphygmic  period  of  ventricular  systole — i.  c.,  to  the  open- 
ing of  the  semilunar  valves.  Measure  the  distance  from  it  to  the  near- 
est vertical  line  that  was  made  to  indicate  the  relative  position  of  the 
writing  points.  Then  measure  off  the  same  distance  in  the  venous  trac- 
ing from  the  corresponding  indicator  line.  This  will  fall  at  the  begin- 
ning of  the  small  wave  (c),  which  is  due  to  the  bulging  into  the  auricles 
of  the  closed  auriculoventricular  valves.     (Pig.  96.) 

273 


274 


THE    CIRCULATION    OF    THE   BLOOD 


The  auricular  "wave  (a)  occurs  one-fifth  of  a  second  in  front  of  c,  and 
may  now  be  ascertained  by  measuring  off  this  distance  in  front  of  c. 
This  is  line  1. 

Now  measure  the  distance  on  the  radial  pulse  tracing  from  the  begin- 
ning of  the  upstroke  to  the  dicrotic  notch.  The  distance  between  these  is 
the  sphygmic  period  (E). 


Fig.  95. — Polysphygmograph.  This  instrument  records  in  ink  on  glazed  paper  two  simul- 
taneous tracings,  i.  e.,  radial  pulse  and  one  other,  such  as  carotid,  jugular,  apex  beat,  etc.,  in  addi- 
tion to  the  time  tracing.  The  ink  tracings  are  both  more  convenient  and  permanent  than  smoked 
paper  tracings.  The  clockwork  operates  at  variable  speeds,  permitting  the  taking  of  protracted 
records   at   different    speeds. 

Measure  off  the  same  distance  on  the  venous  tracing  from  c.  Line 
5  will  be  found  to  fall  just  before  a  small  wave  (v),  which  is  due  to  the 
sudden  opening  of  the  tricuspid  valves.  This  practically  coincides  with 
the  dicrotic  notch  on  the  radial  pulse  tracing.     Sometimes  a  little  wave 


L& 


k  K  i  i; 


Fig.    96. — Xormal    jugular    tracing. 


The    spacing    below    shows    the    duration    of    the    a-c    interval. 
(From    K.    P.    Carter.) 


occurs  on  the  upstroke  of  wave  v  just  where  line  5  falls.  This  co- 
incides with  the  closure  of  the  semilunar  valves.  The  distance  between  it 
and  wave  v  corresponds  to  the  postsphygmic  period. 

The  cause  for  the  depression  (marked  x)  following  c  will  readily  be 
understood  by  referring  to  the  intraauricular  curve  (Fig.  97),  to  Avhich, 
as  already  explained,  the  venous  pulse  tracing  is  qualitatively  similar. 


POLTSPHYGMOGB  IMS 


275 


The  rise  in  the  curve  following  depression  x  is  caused  by  the  filling  «»l 
the  auricle  with  blood.  This  goes  on  until  v,  when  the  tricuspid  valves 
open,  allowing  the  blood  to  fall  into  the  ventricle 


Fig.  97, — Reduced  tracings  from  carotid,  aorta,  ventricle,  auricle  and  jugular,  Jo  show  the 
general  relationships  of  the  various  waves.  An  electrocardiogram  is  also  shown.  Note  that  the 
jugular  and  auricular  curves  have  the  same  contour,  and  that  the  depression  (x)  in  them  occuis 
during    systole    of    the   ventricles.      (After    Lewis.) 

To  interpret  the  cardiogram,  adjust  receiving  tambours  to  the  radial  and 
open  beat  with  both  writing  styles  in  the  same  perpendicular,  and  following 
the  other  directions  described  under  ''venous  pulse"  mark  on  the 
cardiogram:     (See  Fig.  98.) 


^j\jjV*\^ 


r\ 


aJVUvaj  L-A_/\_| 


Fig.  98.— Polysphygmograms  including  jugular,  apex  and  radial  tracings.  Line  4  on  the  radial 
tracing  is  first  of  all  located.  It  is  then  transferred  (by  measurement  from  the  alignment  mark  on 
the  right  edge  of  the  tracing)  to  the  jugular  and  1/10  second  subtracted  from  it,  giving  line  3. 
When  this  is  similarly  transferred  to  the  apex  tracing,  it  falls  somewhere  on  the  upstroke  the  be- 
ginning of   which   is   line   2. 


276  THE    CIRCULATION   OF    THE   BLOOD 

1.  The  beginning  of  the  sphygmic  period  (E)  (line  5). 

2.  The  end  of  the  sphygmic  period  (E)   (line  5). 

3.  The  auricular  wave. 

4.  The  beginning  of  ventricular  systole  (difference  between  1  and  4 
equals  presphygmic  interval). 

5.  The  opening  of  auriculoventricular  valves  (lowest  point  in  tracing). 
Mark  also  on  the  tracing  the  exact  moment  at  which  the  heart  sounds 

are  heard. 

It  is  important  to  make  certain  that  the  button  of  the  tambour  is  ac- 
curately over  the  apex  beat,  since  otherwise  a  depressed  or  negative 
wave  may  be  inscribed  at  ventricular  systole. 

Simultaneous  Arterial  Pulse  Tracings.— The  velocity  of  the  transmis- 
sion of  the  pulse  wave  is  calculated  by  measuring  the  time  between  the 
systolic  rise  in  the  carotid  and  in  the  radial  arteries,  tracings  of  which 
are  taken  by  applying  one  receiving  tambour  to  the  carotid  artery  and 
another  to  the  radial  artery. 

Abnormal  Pulses 

The  following  is  a  brief  description  of  the  main  character  of  abnormal 
pulses: 

The  Ventricular  Pulse. — In  this  no  "a"  waves  are  present  in  the 
jugular  tracing,  the  heart  action  being  either  regular  or  irregular.  In 
the  former  case,  the  absence  of  the  "a"  waves  may  depend  on.-  (1)  over- 
filling of  the  right  auricle,  (2)  increase  in  the  heart  rate,  or  (3)  complete 
heart-block  associated  with  auricular  fibrillation.  When  the  heart  is 
irregular,  the  absence  of  the  "a"  waves  signifies  auricular  fibrillation. 

Delayed  Conduction  and  Heart-block. — This  causes  a  change  in  the 
time  relationship  of  the  "a"  and  "c"  waves  in  the  jugular  curve.  When 
the  heart-block  is  of  the  first  degree,  the  "a-c"  interval  merely  becomes 
lengthened,  but  when  it  is  of  such  degree  that  the  normal  impulse  some- 
times fails  to  be  conveyed  along  the  auriculoventricular  bundle,  isolated 
"a"' waves  can  be  detected.  In  the  higher  degrees  of  heart-block  there 
are  regularly  recurring  "a"  waves  having  no  constant  time  relationship 
to  the  "c"  waves.  For  the  purpose  of  exact  analysis  of  the  curves  in 
suspected  eases  of  delayed  conduction,  it  is  often  advantageous  to  draw 
vertical  lines  below  the  tracing  representing  the  beginning  of  auricular 
and  ventricular  systole.  This  has  been  done  in  the  tracing  reproduced 
in  Fig.  99. 

The  line  joining  these  two  verticals  indicates  the  conduction  time 
or  "a-c"  interval.  When  it  exceeds  one-fifth  of  a  second,  there  is 
delay  in  the  conduction  time. 


POLYSPHYGMOGRAMS 


U7T 


A  tracing  showing  a  higher  degree  of  hearl  block  is  given  in  Pig.  100. 

Sinus  Arrhythmia.  In  this  condition  the  radial  pulse  is  markedly 
irregular,  but  the  "a,"  "c"  and  "v"  waves  of  the  jugular  tracing  occur 
with  the  usual  time  relationship  to  one  another,  and  there  is  no  delay 
in  the  "a"-"c"  interval. 


"^>v 


^k^ 


^TVXVT 


Fig.    V9.~—  Delayed    conduction    time.      First   stage    of   heart-block.      The    A-C    intervals    measure    more 
than   0.2   second.      (From   E.    P.    Carter.) 

Sinus  Bradycardia. — The  beat  originates  at  long  intervals  in  the 
sinus;  the  "a-c"  interval  is  normal,  and  the  radial  pulse  very  slow  but 
practically  regular. 

Premature  Beats. — These  may  be  either  ventricular  or  auricular  in 
origin.  In  the  former  case  the  "a"  waves  on  the  jugular  tracing. space 
regularly  throughout,  but  the  "c"  waves  at  the  point  of  disturbance 


5 


e=r=E=F=ezi    \    \    { 


Sfr,Y- 


-'W 


Fig.    100. — Dropped    beats.      Second    stage    of    heart-block.       (From    E-    P.    Carter.) 

coincide  with  the  "a"  waves,  giving  therefore  a  more  pronounced  wave. 
This  is  due  to  a  premature  contraction  of  the  ventricle  occurring  about 
the  time  of  the  "a"  wave,  so  that  the  latter  finds  the  ventricle  in  a  re- 
fractory state  (see  page  178).  The  premature  contraction  is  therefore 
followed  by  a  compensatory  pause,  which  is  evident  on  the  tracing.  An 
example  of  such  a  case  is  given  in  Fig.  101.    In  doubtful  cases  the  exact 


278 


THE    CIRCULATION    OF    THE   BLOOD 


site  of  origin  of  the  premature  beats  can  be  determined  only  by  careful 

measurement  of  the  distances  between  the  various  beats  of  the  ventricle. 

"Whenever  an  irregularity  repeats  itself  and  the  duration  of  one  cycle 

of  the  arrhythmia  accurately  corresponds  to   another,  the  irregularity 


"** 


-v* 


Tt*,y. 


k  'v  k  k  I  k  k  k  i=B 


"W 


§5 


«-c   -» 


(rt    ^> 


K  k    4-^    ^ 


M    -* 


I'"ig.    101. — Premature   beats    (extrasystoles)    ventricular   in    origin    at   PB.      Compare    the   duration   of 
the  intervals  marked  A   and  B'   with   those  marked   C  and  D.      (From   E.   P.   Carter.) 

may  be  due  to:  (1)  premature  auricular  or  ventricular  contractions; 
(2)  the  occasional  occurrence  of  dropped  beats  (a  failure  of  ventricular 
response)  ;  or  (3)  a  high  degree  of  heart-block  with  a  wide  variation  in 
the  ventricular  response.  The  important  point  to  note  here  is  that,  no 
matter  how  irregular  such  a  tracing  may  appear,  if  the  irregularity  re- 
peats itself  it  can  not  be  due  to  auricular  fibrillation. 


Fig.  102. — Paroxysmal  tachycardia.  The  paroxysms  start  at  x£  following  normal  beats  and 
lasting  for  seven  beats.  The  clue  to  "a,"  which  falls  with  "v"  after  the  first  premature  contrac- 
tions, is  found  in  the  initial   beat  of  the  new  rhythm.      (From   E.   P.   Carter.) 

Paroxysmal  Tachycardia.— "When  the  rate  of  a  regular  pulse  is  sud- 
denly altered  but  the  change  in  rate  bears  a  simple  ratio  to  the  previous 
rhythm,  the  change  may  be  due  to  (1)  premature  ventricular  contrac- 
tions which  do  not  reach  the  radial,  or  (2)  to  the  sudden  development 


]'()I.VS|-HV(JM()(iKA.MS 


279 


of  a  two-iii-one  heart-block.  When  on  the  other  hand,  there  is  no  exact 
ratio  between  the  slow  and  the  rapid  rate,  the  change  is  due  to  the  sud- 
den appearance  or  disappearance  of  paroxysmal  tachycardia.  The 
paroxysms  during  which  the  auricle  is  beating  very  rapidly  may  last  for 
a  variable  time,  such  attacks  persisting  off  and  on  for  hours  or  even  days. 
The  tracing  in  such  a  case  is  given  in  Fig.  102. 


"^MwV 


V^ 


Fig.    103. — Auricular  flutter.      In  this  case   the  ventricular  rate  varied   from   82  to  98  per   minute. 

(From    E.    P.    Carter.) 

Auricular  Flutter. — It  is  impossible  to  diagnose  the  not  infrequent 
existence  of  this  cardiac  condition  without  the  use  of  either  the  poly- 
sphygmogram  or  the  electrocardiogram.  The  jugular  curve  may  be  of 
two  types,  one  made  up  of  rapid,  more  or  less  uniform  waves,  the  other 
of  waves  that  are  paired  with  a  constant  time  interval  between  the  pairs. 


"$^>i  ^n\;< 


I|II^III|1IUIIIL[1JJJ 


VA  >r*wy; 


y-\    v-\    v-\    vN    v-\ 


Fig.    104. — Auricular    flutter.      Note    the    relative    rates    of    A    and    V,    and    also    that    the    ventricular 
rate  is  regular.      (From   E.   P.   Carter.) 

All  of  the  frequent  beats  of  the  auricle  do  not  reach  the  ventricle  in  this 
condition,  so  that  the  ratio  between  auricular  and  ventricular  beats 
may  be  1:3  or  1:4.  The  condition  must  therefore  not  be  confused  with 
heart-block,  the  main  point  of  distinction  being  that  in  the  latter  condi- 
tion the  ventricular  pulse  is  slow  and  the  auricular  about  normal.     The 


280 


THE    CIRCULATION    OF    THE    BLOOD 


radial  pulse  may  be  regular  or  irregular.  The  cause  for  the  failure  of 
every  auricular  beat  to  travel  to  the  ventricle  during  auricular  flutter 
is  partly  the  refractory  condition  of  the  bundle,  and  partly  the  refrac- 
tory phase  of  ventricular  contraction.  The  bundle  may  be  considered 
as  a  narrow  bridge  which  will  transmit  the  impulses  across  it  only  at  a 
certain  rate.  If  the  impulses  arrive  too  rapidly,  only  some  of  them  can 
cross  the  bridge,  and  even  of  those  that  do  cross,  a  limited  number  only 
will  find  the  ventricle  in  a  condition  of  excitability  because  of  the  re- 
fractory period   (see  page  178).     Tracings  showing  auricular  flutter  are 


"WAxWA  . 


d 


MfV\\-.<SAvr 


M 


V 


5»\ 


^     |  \v 


n  iv 


Fig.  105. — Auricular  fibrillation.  Note  the  absence  of  all  "a"  waves  from  the  jugular  tracing,  the 
marked  irregularity  of  the  radial  pulse,  and  the  occurrence  of  "c"  and  "v"  during  the  sphygmic 
period.      (From    K.    P.    Carter.) 

given  in  Figs.  103  and  104.     In  one  of  them  the  radial  pulse  is  regular; 
in  the  other,  irregular. 

Auricular  Fibrillation. — The  contractions  of  the  auricle,  as  already  ex- 
plained, are  entirely  irregular,  so  that  the  jugular  tracings  show  an  en- 
tire absence  of  all  "a"  waves,  the  radial  tracing  being  characterized  by 
the  complete  absence  of  a  dominant  rhythm  and  by  great  variation  in  the 
length  of  the  individual  beats  from  one  cardiac  cycle  to  the  next.  This 
irregularity  does  not  repeat  itself,  and  the  long  pauses  are  not  simple 
multiples  of  the  shortest  pause.  Tracings  from  a  case  of  auricular 
fibrillation  are  shown  in  Fig.  105. 


CHAPTEB  XXXII 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGIC 

METHODS  (Cont'd) 

THE  MEASUREMENT  OF  THE  MASS  MOVEMENT  OF  THE  BLOOD 

Method. — The  apparatus  used  for  this  purpose  consists  essentially  of 
a  vessel  containing  a  known  quantity  (3,000  c.c.)  of  water  and  a  ther- 
mometer from  which  a  change  of  temperature  of  a  hundredth  of  a  de- 
gree centigrade  can  be  read.  In  order  to  diminish  as  much  as  possible 
the  loss  of  heat  between  the  vessel  and  the  outside  air,  the  walls  are 
double,  the  spaee  between  being  stuffed  with  broken  cork.  The  top  of 
the  vessel  is  closed  with  a  thick  cork  plate,  having  suitable  openings  in 
it  for  the  hand  or  foot  and  for  the  thermometer  and  a  stirrer  (feather) 
with  which  to  keep  the  water  in  constant  motion.  The  apparatus  is  called 
a  calorimeter. 

After  the  hand  or  foot  has  been  in  the  calorimeter,  with  the  water  a 
few  degrees  below  that  of  the  body,  for  a  certain  time  (ten  minutes),  the 
temperature  of  the  water  Avill  of  course  become  raised,  and  the  degree 
to  which  this  occurs,  multiplied  by  the  volume  of  the  water  in  cubic 
centimeters,  will  give  in  calories  the  amount  of  heat  dissipated.  By  the 
application  of  a  very  simple  formula  it  is  now  an  easy  matter  to  calculate 
how  much  blood  must  have  passed  through  the  blood  vessels  of  the  part 
in  order  to  give  out  the  observed  amount  of  heat;  for,  if  we  divide  the 
calories  by  the  difference  in  temperature  between  the  inflowing  and  out- 
flowing blood  of  the  part,  the  result  must  indicate  the  volume  of  blood,  in 
cubic  centimeters,  that  has  passed  through  it  (since  by  definition  a  calorie 
equals  volume  multiplied  by  difference  in  temperature).  It  remains  to 
explain  the  equation  by  which  the  results  are  arrived  at.  If  (J  equals  the 
amount  of  blood,  II  the  calories  of  heat  given  out  to  the  calorimeter,  T 
the  temperature  of  the  arterial  blood  and   T'    the  temperature  of  the 

venous  blood,  then  we  have  the  equation :    Q=™ — ^7.    It  has  been  shown 


*For  the  determination  of  H  we  must  multiply  the  cubic  centimeters  of  water  plus  the  water 
equivalent  of  the  hand  and  calorimeter  (because  both  of  these  will  absorb  some  heat)  by  the  dif- 
ference in  temperature  plus  the  self-cooling  of  the  calorimeter  (because  some  heat  is  lost  to  the 
air  during  the  observation).  The  water  equivalent  of  the  hand  is  equal  to  its  volume  multiplied 
by  0.8;  that  of  the  calorimeter  must  be  determined  for  each  instrument  and  is  usually  about  100  c.c. 
The  self-cooling  of  the  calorimeter  is  determined  by  observing  the  fall  in  temperature  for  a  period 
equal  to  that  of  the  actual  observation  without  the  hand  in  the  calorimeter. 

281 


282  THE    CIRCULATION   OF    THE   BLOOD 

by  Stewart  that  T  may  be  taken  as  the  same  as  that  of  the  mouth,  or  0.5° 
C.  below  that  of  the  rectum,  and  T'  as  the  average  temperature  of  the 
water  in  the  calorimeter  during  the  observation.    To  allow  for  the  specific 

heat  of  blood,  the  result  is  multiplied  by-^-,  the  reciprocal  of  the  specific 
heat  of  blood. 

Theoretically,  then,  the  method  is  very  simple,  and  there  are  no  un- 
usual technical  difficulties  in  applying  it.  The  only  special  precaution 
is  that  the  air  surrounding  the  calorimeter  should  be  kept  fairly  con- 
stant in  temperature,  so  that  we  may  be  enabled  to  allow  in  our  calcula- 
tions for  the  loss  of  heat  from  the  calorimeter  itself,  this  value  being 
obtained  by  observing  the  change  of  temperature  in  the  calorimeter  for 
a  certain  period  of  time  after  the  hand  has  been  removed  from  it. 

The  Normal  Flow 

The  results  are  calculated  on  the  basis  of  grams  of  blood  flowing 
through  100  c.c.  of  tissue  in  one  minute.  The  volume  of  the  hand  or  foot 
is  ascertained  by  placing  it  in  water  contained  in  a  small-sized  irrigation 
can,  the  tube  of  which  is  connected  with  a  burette.  The  height  to  which 
the  water  rises  in  the  burette  is  noted,  and  after  withdrawing  the  hand, 
water  is  added  from  a  graduate  to  the  irrigation  can  until  the  same 
height  is  reached  on  the  burette.  The  number  of  cubic  centimeters  re- 
quired gives  the  volume  of  the  hand.  In  a  normal,  healthy  individual 
the  average  flow  in  the  hand  is  from  12  to  13  gm.  for  the  right  hand, 
and  about  half  a  gram  less  for  the  left.  This  difference  between  the  two 
hands  corresponds,  of  course,  with  their  relative  degree  of  development. 
The  average  foot  flow  is  much  less,  and  varies  according  to  whether  the 
patient  is  sitting  up  or  lying  down  while  the  measurement  is  being  made. 
In  a  normal  individual,  while  lying  down,  it  was  5.11  gm.  in  the  right 
foot  and  5.23  gm.  in  the  left,  per  100  c.c.  of  foot;  but  only  2.96  gm.  for 
the  right  and  4.1  gm.  for  the  left  foot,  while  sitting  up.  The  results  have 
been  found  to  undergo  only  a  slight  variation  from  month  to  month  in  a 
given  healthy  individual,  provided  the  air  temperature  during  the  dif- 
ferent observations  is  the  same  and  the  person  has  been  some  time  in  the 
room  before  the  observations  are  begun.  This  precaution  is  especially 
important  if  he  is  a  dispensary  patient  and  has  been  in  the  open  air  with 
bare  hands.  The  flow  varies  in  different  individuals  both  with  regard 
to  absolute  amount  and  the  ratio  between  the  two  hands  or  feet.  When 
the  total  flow  in  the  hands  is  compared  with  th'at  in  the  feet,  a  ratio  of 
about  3  to  1  is  usually  obtained. 

The  Physiologic  Causes  for  Variations  in  Bloodflow. — As  above  indicated, 
the  most  marked  of  these  is  probably  the  temperature  of  the  room.     The 


MEASUREMENT   OF    MASS    MOVEMENT   OF    BLOOD  283 

temperature  of  the  water  in  the  calorimeter  has  Likewise  a  great  influence, 
and  for  the  comparison  of  different  eases  it  is  always  important  that  the 
room  and  calorimeter  temperatures  be  stated  alongside  the  results.  Muscular 
contractions,  produced  by  moving  the  fingers  in  the  calorimeter,  cause  a 
marked  increase  in  flow,  accompanied  by  a  diminished  flow  in  the  hand 
that  was  at  rest.  A  great  diminution  of  flow  results  from  constriction  of 
the  arm  of  sufficient  degree  to  obstruct  the  venous  circulation;  and  when 
the  constriction,  as  that  caused  by  a  blood  pressure  armlet,  is  increased  to 
between  the  systolic  and  diastolic  pressures,  extremely  little  blood  flows 
through  the  hand. 

By  immersing  the  opposite  hand  or  foot  in  hot  or  cold  water,  the  blood- 
flow  through  the  observed  hand  increases  or  decreases,  respectively. 
The  change  may  be  of  a  temporary  character,  or  it  may  persist  through- 
out the  whole  period  of  immersion  of  the  hand.  These  reactions  are  due 
to  a  vascular  reflex,  and  observations  of  its  sensitiveness  are  of  value  in 
the  study  of  the  effects  of  lesions  either  of  the  nerve  or  of  the  nerve 
centers  concerned  in  vascular  reflexes. 

Clinical  Conditions  which  Affect  the  Bloodflow 

Even  in  cases  where  there  is  plenty  of  other  evidence  of  curtailment 
of  flow,  the  measurement  may  be  of  importance  either  for  detecting 
an  alteration  in  the  vascular  reflex  or,  by  comparison  of  the  two 
hands,  for  demonstrating  the  relative  degree  of  alteration  in  flow.  In 
acute  inflammatory  conditions  affecting  one  hand,  there  is  an  increase 
in  flow  on  the  affected  side  accompanied  by  a  marked  curtailment  on 
the  other  side.  This  indicates  that  an  increased  flow  in  the  infected 
area  is  accompanied  by  a  reflex  vasoconstriction  elsewhere,  particu- 
larly in  the  symmetrically  placed  part  of  the  opposite  side  of  the 
body.  In  cases  of  nonbacterial  inflammation  of  the  hand,  as  in  gout, 
no  sign  of  vasoconstriction  may  be   observed. 

There  are  many  clinical  conditions  in  which  Stewart's  method  re- 
veals an  alteration  in  bloodflow  that  would  be  unsuspected  by  the  use 
of  ordinary  clinical  methods.  It  is  for  the  investigation  of  these  that 
the  method  is  of  greatest  value.  The  most  important  findings  are  as 
follows: 

Anemia. — The  bloodflow  in  the  hand  may  be  much  less  than  normal 
in  pernicious  anemia  and  secondary  anemia,  and  distinctly  curtailed 
in  chlorosis.  Since  the  minute  volume  of  the  heart  is  also  increased 
in  these  conditions,  the  vasoconstriction  at  the*  periphery  will  assist 
in  compelling  more  blood  to  pass  through  the  lungs,  so  as  to  make  up 
for  deficiency  of  blood. 


284  THE    CIRCULATION   OF   THE   BLOOD 

Fever. — Since  changes  in  the  cutaneous  circulation  probably  con- 
stitute the  chief  factor  in  the  derangement  of  the  temperature-regu- 
lating mechanism  in  fever  (cf.  page  723),  it  is  evidently  of  great  ;i<1- 
vantage  to  be  able  to  measure  such  changes  quantitatively.  This  has 
been  done  by  Stewart  in  several  cases  of  typhoid  fever  and  in  one  case 
of  pneumonia.  In  general  it  was  found  that  the  flow  in  the  feet  never 
exceeded  the  normal  flow,  and  was  usually  much  below  it.  This  ten- 
dency to  vasoconstriction  seems  to  be  carried  into  convalescence.  For 
practical  reasons  the  handflow  has  not  been  so  extensively  studied. 
This  hyperexcitability  of  the  vasoconstrictor  mechanism  at  the  periph- 
ery is  most  naturally  interpreted  as  a  defensive  reaction  of  the  or- 
ganism by  which  an  increased  supply  of  blood  is  imported  to  those 
internal  organs  which  bear  the  brunt  of  the  infection.  When  we  con- 
sider that  in  spite  of  this  constriction  of  the  periphery  the  blood  pres- 
sure is  low  and  the  pulse  dicrotic,  Ave  must  conclude  that  there  is  con- 
siderable dilatation  of  other  vascular  parts,  especially  the  splanchnic 
are;1..  A  very  practical  application  of  these  facts  presents  itself  in  con- 
sidering the  rationale  of  the  cold-bath  treatment  for  fever.  If,  for 
example,  we  conclude  that  the  cutaneous  constriction  is  in  the  inter- 
ests of  an  increase  in  the  bloodflow  to  the  organ  on  which  the  stress 
of  the  infection  falls,  it  will  evidently  be  more  rational  to  lower  the 
temperature  by  methods  which  will  not  diminish,  and  may  even  in- 
crease, the  cutaneous  constriction  than  to  do  so  by  causing  the  vessels 
to  dilate.  In  other  words,  the  use  of  antipyretics  seems  to  be  contra- 
indicated,  since  they  diminish  the  body  temperature  by  causing  vaso- 
dilatation at  the  periphery  with  a  consequent  withdrawal  of  blood 
from  the  seat  of  infection. 

Cardiovascular  Diseases. — In  cardiac  cases  the  handflow  is  far  more 
apt  to  be  markedly  deficient  where  there  is  evidence  of  serious  impair- 
ment of  the  myocardium  than  in  cases  where  a  gross  valvular  lesion 
exists  but  the  heart  action  is  strong  and  orderly.  This  indicates  that 
it  is  more  serious  for  the  force  of  the  heart  pump  to  be  interfered 
with  than  for  its  valves,  particularly  the  mitral,  to  be  leaky.  Even 
where  there  is  considerable  venous  engorgement,  the  flow  may  be  lit- 
tle diminished.  In  untreated  cases  of  auricular  fibrillation  the  blood- 
flow  is  subnormal.  After  the  administration  of  digitalis  the  bloodflow 
in  such  cases  is  often  promptly  and  decidedly  increased. 

As  would  be  expected,  arteriosclerosis  is  associated  with  a  small  blood- 
flow, and  the  vasomotor  reflexes  are  weaker  than  in  normal  persons. 

In  aortic  aneurism,  "when  the  aneurism  is  of  such  a  size  as  to  cause 
pressure  on  the  subclavian  artery  or  vein,  there  is  a  diminution  in  flow 
of  the  corresponding  hand,  but  aortic  aneurism  itself,  although  it  may 


MEASUREMENT   OF    mass    MOVEMENT   OF    BLOOD  285 

cause  great  changes  in  the  character  of  the  pulse  beat,  dues  not  decid- 
edly affect  the  mass  movement  <>i"  the  blood.  In  aneurism  of  the  sub- 
clavian artery,  the  bloodflow  may  lie  much  greater  in  the  corresponding 
than  in  the  opposite  hand,  even  though  the  amplitude  of  the  pulse  is 
very  obviously  diminished  and  the  difference  between  the  systolic,  and 
diastolic  pressures  (the  pressure  pulse)  is  much  less  on  the  affected 
than  on  the  normal  side.  By  ordinary  clinical  measurements,  there- 
fore, Ealse  estimates  of  bloodflow  are  quite  likely  to  he  made.  These 
results  are  no  doubt  owing  partly  to  vasodilatation  brought  about  by 
pressure  of  the  aneurism  on  the  brachial  plexus  and  partly  to  the 
lower  resistance  to  the  flow  of  blood  into  Hie  dilated  subclavian. 

In  Raynaud's  disease,  as  would  be  expected,  the  flow  is  small,  the 
diminution  being  more  or  less  proportional  to  the  duration  of  Hie 
disease.  The  contralateral  vasomotor  reaction  to  cold  is  also  pecu- 
liarly intense. 

In  diabetic  gangrene  of  the  feet  there  is  a  very  subnormal  flow  in  both 
the  hands  and  the  feet.     The  vasomotor  reflexes  are  also  feeble. 

It  is  sometimes  difficult  to  tell  whether  an  observed  curtailment  of 
flow  is  a  nervous  (reflex)  effect  or  is  due  to  some  mechanical  interfer- 
ence. There  are  two  ways  by  which  the  exact  cause  may  be  diagnosed: 
(1)  by  observing  the  flow  from  day  to  day;  if  it  remains  unchanged, 
any  alteration  must  be  dependent  on  mechanical  causes;  (2)  by  observ- 
ing the  change  in  flow  brought  about  by  altering  the  temperature  of  the 
room  or  calorimeter  and  seeing  whether  the  ratio  between  the  two  hands 
remains  unchanged  or  becomes  altered.  If  the  latter  occurs,  the  in- 
equality in  flow  must  be  due  to  nervous  causes. 

Diseases  of  the  Nervcus  System. — The  effect  of  neuritis  on  the  flow 
varies  with  the  duration  of  the  disease.  In  cases  of  early  peripheral 
unilateral  neuritis  there  may  be  an  increase  of  flow  altering  the  ratio  be- 
tween the  two  hands  with  the  greater  flow  on  the  diseased  side.  In 
neuritis  of  long  standing  the  flow  is  cut  down,  the  greater  flow  occurring 
on  the  healthy  side.  The  changes  here  are  probably  due  to  anatomic 
alterations  in  the  lumen  of  the  tube,  perhaps  a  thickening  of  the  intima. 
In  motor-neuron  disease  without  any  involvement  of  the  sensory  skin 
nerves  the  flow  seems  to  remain  normal  and  the  reflexes  to  be  well- 
marked.  This  indicates  that  involvement  of  the  motor  nerves  does  not 
interfere  with  bloodflow  to  anything  like  the  same  degree  as  involvement 
of  the  skin  nerves. 

Hemiplegia. — A  deficiency  of  bloodflow  of  the  paralyzed  side  is  usually 
observed,  and  the  vasomotor  reflexes  are  altered,  the  most  usual  change 
being  that  vasoconstriction  is  more  easily  produced  than  vasodilatation. 


2S6  THE    CIRCULATION   OP   THE   BLOOD 

In  some  cases  an  abnormal  tendency  to  vasoconstriction  is  a  conspicuous 
feature. 

Tabes  Dorsalis. — The  flow  is  distinctly  diminished,  especially  in  the 
feet,  although  also  in  the  hands,  and  the  vasomotor  reflexes  are  feeble. 
Sometimes  there  is  inequality  in  the  flow  of  the  two  hands,  which  how- 
over  need  not  necessarily  indicate  a  unilateral  lesion  of  the  cord  in  the 
cervical  region. 


CHAPTER  XXXIII 
SHOCK 

Shock  may  be  due  to  a  variety  of  causes.  In  general  it  may  be  de- 
scribed as  a  condition  in  which  there  is  more  or  less  paralysis  of  the 
sensory  and  motor  portions  of  the  reflex  arc,  along  with  profound  dis- 
til rbanccs  in  the  circulatory  system,  subnormal  temperature,  frequent 
and  shallow  respiration,  and  more  or  less  unconsciousness.  Certain  of 
these  symptoms  may  be  considered  as  primary  and  others  as  secondary, 
an  important  step  in  the  investigation  of  this  difficult  and  important 
problem  being  to  distinguish  between  the  two  groups.  Before  attempt- 
ing to  do  this,  however,  it  will  be  profitable  to  differentiate  as  sharply 
as  possible  the  various  conditions  in  which  one  or  another  of  the  many 
varieties  of  shock  is  said  to  occur. 

The  following  varieties  of  shock  have  been  described: 

1.  Gravity  Shock. — This  is  caused  by  the  stagnation  of  blood  in  the 
splanchnic  vessels  and  the  consequent  inadequate  filling  of  the  heart  in 
diastole.  It  occurs,  when  the  erect  position  is  assumed,  in  animals  in 
which  the  mechanism  which  ordinarily  compensates  for  the  tendency  of 
gravity  to  make  the  blood  flow  to  the  dependent  parts  is  inadequate. 
Thus,  when  a  domesticated  rabbit  with  a  large  pendulous  abdomen  is 
held  in  the  vertical  tail-down  position  for  any  length  of  time,  the  animal 
gradually  passes  into  a  shocked  condition  and  may  die  in  a  short  time 
(20  to  30  minutes).  Observation  of  the  blood  vessels  of  the  ear  or  a 
record  of  arterial  blood  pressure  will  show  that  the  cause  of  shock  in 
this  case  has  been  a  great  curtailment  of  the  blood  supply  to  the  upper 
part  of  the  body,' and  therefore  to  the  nerve  centers  (Fig.  244).  The 
shock  is  entirely  dependent  upon  the  laxity  of  the  abdominal  muscula- 
ture, for  if  a  binder  is  applied  to  the  abdomen,  or  if  the  experiment  is 
performed  on  a  rabbit  whose  abdominal  musculature  is  in  good  condi- 
tion, gravity  shock  does  not  develop.  Nor  can  fatal  gravity  shock  be 
produced  in  a  dog,  although  in  a  deeply  anesthetized  animal  a 
marked  fall  in  arterial  blood  pressure  occurs  when  the  vertical  tail- 
down  position  is  assumed.  In  man,  in  whom  compensation  for  the  erect 
posture  is  highly  developed,  shock  from  gravity  occurs  only  when  there 
has  been  some  other  considerable  upset  in  the  circulatory  mechanism 
(see  also  page  245). 

287 


288  THE    CIRCULATION    OP    THE   BLOOD 

2.  Hemorrhagic  Shock. — Free  hemorrhage  produces  a  typical  condi- 
tion of  shock,  but  the  extent  to  which  different  individuals  react  to  the 
same  degree  of  hemorrhage  varies  considerably.  The  essential  factor  in 
the  production  of  hemorrhagic  shock  is  of  course  similar  to  that  of  grav- 
ity shock — namely,  a  deficient  diastolic  filling  of  the  heart  with  blood. 
Details  concerning  the  effect  of  hemorrhage  will  be  found  elsewhere 
(page  135). 

3.  Anesthetic  Shock. — So  far  as  blood-pressure  reflexes  are  concerned, 
an  animal  can  be  kept  in  a  perfect  condition  when  ether  is  administered 
in  just  sufficient  amount  to  produce  light  anesthesia.  When  larger 
quantities  of  ether  are  employed,  a  typical  condition  of  shock  is  almost 
certain  to  supervene  after  a  time.  In  such  instances  the  arterial  blood 
pressure  remains  low  and  can  not  be  restored  even  after  an  hour  or  two 
of  artificial  respiration.  There  is,  however,  a  difference  between  ether 
shock  and  the  variety  which  we  shall  discuss  later  under  the  title  of 
surgical  shock :  in  the  former,  removal  of  the  anesthetic  causes  all  reflexes  to 
return,  whereas  in  surgical  shock  most  of  these  are  subnormal.  The  danger 
of  anesthetic  shock  has  been  considerably  diminished  in  the  clinic  by 
the  more  careful  administration  of  ether  or  by  the  use  of  other  anesthet- 
ics, such  as  nitrous  oxide  gas.  A  condition  closely  simulating  shock 
may  also  be  induced  in  the  earlier  stages  of  the  administration  of  anes- 
thetics when  these  are  badly  given,  but  paralysis  of  the  heart  or  of  the 
respiratory  center  is  a  usual  contributory  cause. 

4.  Spinal  Shock. — Spinal  shock  is  produced  by  section  of  the  spinal 
cord,  but  it  is  to  be  carefully  distinguished  from  all  other  forms  of  shock 
because  of  its  local  character,  as  it  affects  only  those  parts  of  the  body 
which  lie  below  the  level  of  the  lesion  in  the  cord.  Above  this  level  the 
animal  may  be  in  a  perfectly  normal  condition,  except  in  cases  where 
the  section  has  been  at  so  high  a  level  that  it  has  severed  the  vasocon- 
strictor pathway  and  thereby  produced  a  fall  in  blood  pressure  from 
vasodilatation.  Even  when  this  has  happened  the  part  of  the  animal 
anterior  to  the  spinal  lesion  is  by  no  means  in  a  condition  of  shock.  Thus, 
Sherrington  observed  in  a  monkey  whose  spinal  cord  had  been  cut  far 
forward  that,  although  the  posterior  part  of  the  body  was  in  profound 
spinal  shock  and  the  blood  pressure  very  low,  the  animal  amused  him- 
self by  catching  flies  with  his  hands.  A  sufficient  description  of  the  con- 
dition of  spinal  shock  has  been  given  elsewhere,  but  here  it  may  be  noted 
that  it  consists  essentially  in  a  paralysis  involving  at  first  all  of  the  re- 
flex mechanisms,  including  the  control  of  the  sphincters,  in  the  part  of 
the  cord  posterior  to  the  section.  In  the  course  of  a  few  days  or  weeks, 
according  to  the  position  of  the  animal  in  the  scale  of  development,  the 
reflexes  gradually  return,  until  ultimately  in  a  couple  of  months — in  a 


shock  289 

dog,  for  example — they  may  all  have  reappeared.  The  cause  of  this 
shock  is  no  doubt  the  sudden  interruption  of  the  nervous  pathways 
which  reflex  action  ordinarily  takes  in  the  higher  animals  (see  page  803). 

5.  Nervous  Shock;  "Shell  Shock."— Considerable  attention  has  been 
paid  to  the  nervous  shock  that  has  frequently  been  observed  in  men  who 
have  been  subjected  to  the  harrowing  sights  and  the  constant  noise  and 
nerve  strain  incurred  in  modern  warfare.  The  symptoms  may  appear 
suddenly  at  the  front  or  they  may  develop  in  men  who  have  comported 
themselves  in  an  apparently  normal  manner  until  removed  to  the  rear, 
when  they  pass  into  a  condition  more  or  less  simulating  that  of  shock. 
Severe  conditions  may  also  result  to  soldiers  from  injuries  which  in  nor- 
mal individuals  would  not  in  themselves  be  sufficient  to  produce  sur- 
gical shock.  The  characteristic  symptoms  in  such  cases  are  entirely 
different  from  those  of  other  forms  of  shock,  and,  as  has  been  shown  by 
Elliot-Smith  and  T.  H.  Pear,25  the  condition  must  be  treated  from  the 
neurologic  or  psychopathic  point  of  view. 

6.  Surgical  Shock. — It  is  this  variety  that  is  usually  referred  to  when 
one  speaks  of  shock.  It  may  be  produced  either  by  severe  mechanical 
injury  to  a  healthy  person  or  by  extensive  manipulation  and  rough 
handling  on  the  operating  table.  It  is  common  in  trench  warfare,  be- 
ing therefore  an  important  variety  of  "shell  shock,"  which  term  must 
be  used  only  in  a  general  sense.  However  produced,  the  symptoms  of 
surgical  shock  are  very  much  the  same.  The  patient  lies  in  a  quiet, 
apathetic  condition,  caring  little  for  what  is  going  on  around  him,  and 
answering  questions  only  when  repeatedly  and  importunately  questioned. 
His  skin,  lips  and  gums  are  very  pale  and  more  or  less  cyanotic ;  the  skin 
feels  cold  and  is  moist  with  sweat;  the  reflexes  are  greatly  diminished, 
and  it  is  usually  only  after  applying  a  very  painful  stimulus  that  any 
movement  of  defense  is  elicited  or  resentment  is  shown  on  the  part  of  the 
patient.  The  postural  reflexes  are  also  abolished,  so  that  if  a  limb  is 
lifted  it  falls  back  limp  and  toneless.  The  pulse  at  the  wrist  is  very 
rapid,  thin  and  almost  imperceptible,  and  the  arterial  blood  pressure  is 
abnormally  low.  The  respirations  are  frequent  and  shallow.  The  rec- 
tal temperature  is  1°  C.  or  more  below  normal.  The  pupils  are  dilated 
and  react  slowly  to  light.  When  he  can  be  induced  to  speak,  the  pa- 
tient's voice  is  hoarse,  and  he  complains  of  cold  and  numbness  in  the 
extremities.     The  symptoms  are  not  unlike  those  of  cholera. 

Experimental  Investigations  of  Shock 

For  inducing  shock  experimentally,  two  general  methods  have  been 
employed:  either  rough  manipulation  of  the  abdominal  viscera,  or  re- 


290  THE    CIRCULATION    OP    THE   BLOOD 

peated  stimulation  of  large  afferent  nerves.  Since  the  experiments  are 
usually  performed  on  anesthetized  animals,  the  effect  of  the  anesthetic 
has  to  be  discounted  in  experimental  work  on  the  causes  of  shock. 

The  first  step  in  such  an  investigation  is  naturally  to  classify  the 
symptoms  into  primary  and  secondary,  for  on  the  success  of  the  classi- 
fication must  depend  the  outcome  of  further  investigation  into  the 
problem. 

The  earlier  investigators  were  naturally  attracted  to  the  pronounced 
fall  in  Mood  pressure  as  the  primary  cause  of  shock.  It  is  true  that  a 
pronounced  lowering  will  ultimately  produce  symptoms  that  are  not 
unlike  those  of  shock,  but  on  the  other  hand  it  can  readily  be  shown  that 
this  is  a  result  only — a  symptom  and  not  a  cause  of  the  condition.  It 
was  believed  by  Crile  that  the  fall  in  blood  pressure  depended  on  a 
universal  dilatation  of  the  blood  vessels  caused  by  exhaustion  of  the  tone 
of  the  vasoconstrictor  center.  It  has  been  clearly  shown,  however,  that 
the  tone  of  this  center  is  practically  normal  in  shock,  and  that  the  arte- 
rioles are  maintained  not  in  a  dilated  but  in  a  contracted  state,  indicat- 
ing clearly  therefore  that  the  low  blood  pressure  must  be  dependent 
upon  inadequate  output  of  blood  from  the  heart.  The  evidence  for  this 
conclusion  is  as  follows:  (1)  W.  T.  Porter26  and  his  collaborators  have 
shown  that  both  pressor  and  depressor  reflexes  are  perfectly  normal 
in  a  rabbit  that  is  in  a  condition  of  extreme  shock.  It  is  particularly  im- 
portant that  depressor  effects  were  still  obtained,  since  this  indicates 
that  tonic  activity  of  the  center  must  still  have  been  present.  (2)  The 
blood  vessels  in  a  shocked  animal  are  in  a  contracted  state.  On  opening 
a  vessel  and  observing  the  outflow  of  blood,  an  increase  occurs  when  the 
nerve  to  the  blood  vessel  is  cut.  (3)  This  same  fact  has  been  shown  by 
Seelig  and  Joseph,27  who  cut  the  vasomotor  nerve  proceeding  to  the 
vessels  of  one  ear  of  a  white  rabbit  and  thus  caused  a  local  paralytic 
dilatation  of  the  vessels.  Intense  shock  was  then  produced  in  the  animal 
in  the  usual  way,  after  which  the  blood  pressure  in  the  anterior  part  of 
the  animal  was  suddenly  raised  by  applying  a  clamp  to  the  abdominal 
aorta  just  below  the  diaphragm..  This  increased  blood  pressure  caused 
the  vessels  of  the  denervated  ear  to  become  engorged  with  blood,  but' 
not  those  of  the  opposite  normal  ear,  which  retained  their  tone  (Fig. 
106).  (4)  The  volume  of  blood  expelled  by  the  ventricles  has  been 
shown  by  Henderson28  to  be  distinctly  diminished  in  the  early  stages  of 
shock,  the  lack  of  pronounced  fall  in  blood  pressure  indicating  that  there 
must  be  a  compensatory  constriction  of  the  arterioles.  Lastly  (5),  it 
has  been  found  by  Morrison  and  Hooker29  that  the  outflow  of  blood 
from  the  perfused  organs  of  a  shocked  animal  is  less  than. that  from  the 


\ 


Fig.  106. — Illustration  showing  the  appearance  of  the  blood  vessels  in  the  ,  ears  of  a  rabbit 
"in  a  state  of  deep  shock."  The  marked  vasoconstriction  is  very  plain  in  the  left  ear.  the  ves- 
sels of  the  right  ear  being  dilated  because  the  cervical  sympathetic,  which  carries  the  constrictor 
libers,   has  been  cut.      (From   Seelig   and  Joseph.) 


shock 


291 


same  organs  under  normal  conditions".     Furthermore,  severing  of  the 
nerve  of  such  an  organ  causes  an  increased  out  How. 

To  these  various  pieces  of  evidence  of  a  constricted  condition  of  at 
least  certain  of  the  vessels  in  shock,  may  be  added  the  less  direct  evi- 
dence furnished  by  the  pallor  of  the  shocked  patient  and  the  indications 
that  the  sympathetic  nervous  system,  instead  of  being  paralyzed,  is 
in  an  excited  state,  as  shown  by  the  sweating  and  the  dilated  pupils. 
Furthermore,  we  know  from  the  experiments  of  Pike,  Guthrie  and 
Stewart''"  on  the  resuscitation  of  the  nerve  centers  after  interference 
with  the  circulation  to  the  brain,  that  the  vasomotor  center  is  remark- 
ably resistant  to  anemia.  It  can  withstand  this  condition  without  losing 
its  tone  oi'  reflex  activity  better  than  any  of  the  other  cardinal  centers. 
Those  who  have  maintained  that  a  deficiency  in  the  tone  of  the  vaso- 
constrictor and  other  nerve  centers  is  responsible  for  shock  have  based 
their  evidence  partly  on  histologic  examination  of  nerve  cells  of  shocked 
animals,  it  being  assumed  that  the  chromatolysis  shown  by  these  cells 
indicates  an  exhausted  condition.  The  assumption  is,  however,  entirely 
unwarranted,  and  no  regard  is  given  to  the  well-established  fact  that 
similar  histologic  changes  may  be  produced  by  other  conditions.  It 
is  certainly  safe  to  conclude  that  the  changes  in  the  nerve  cells  in  shock 
are  the  result  and  not  the  cause  of  the  low  blood  pressure  of  this 
condition. 

Since  the  fall  in  arterial  blood  pressure  occurs  with  contracted  ar- 
terioles, it  must  be  dependent  on  a  diminished  discharge  of  blood  from 
the  heart.  Interference  with  the  heart  action  itself  (independently  of 
the  blood  carried  to  this  organ),  or  a  deficiency  in  the  filling  of  the  ven- 
tricles during  diastole, — that  is,  a  stasis  of  blood  in  the  venous  or  cap- 
illary areas, — are  the  possible  causes  for  the  diminished  output.  The 
possibility  that  the  heart  action  itself  has  been  interfered  with,  as  by 
paralysis  of  the  vagus  mechanism,  causing  a  rapid  beating  of  the  heart, 
has  been  shown  to  be  untenable  by  various  experiments.  After  stimulat- 
ing the  central  end  of  an  uncut  vagus  nerve  in  the  neck  in  shock,  the 
reflex  vagus  mechanism  is  still  operative.  Furthermore,  when  the  arte- 
rial blood  pressure  is  artificially  raised,  either  by  epinephrine  injection 
or  by  cerebral  compression,  the  heart  promptly  responds  to  the  in- 
creased blood  pressure  by  contracting  more  sloAvly  and  vigorously. 
Evidently,  therefore,  as  the  cardiac  mechanism  itself  is  normal,  the  de- 
ficient discharge  of  blood  must  be  dependent  upon  improper  diastolic 
filling.  After  this  condition  has  set  in,  it  becomes  progressively  worse 
because  of  weakening  of  the  heart  muscles  consequent  upon  the  failing 
blood  supply  through  the  coronary  vessels. 

The  question  therefore  narrows  itself  down   to  the  cause  of  the  ineffi- 


292  THE    CIRCULATION    OF    THE   BLOOD 

cient  return  of  venous  blood  to  the  heart.  In  the  first  place,  let  us  see 
whether  shock  can  be  produced  experimentally  in  animals  by  mechanical 
interference  with  the  bloodflow  in  the  vena  cava.  That  such  is  the  case 
was  shown  by  H.  H.  Janeway  and  Jackson,31  who  found  that  mechanical  ob- 
struction of  the  inferior  vena  cava  for  a  short  time  was  followed  by  the  usual 
signs  of  shock.  Such  interference  with  the  venous  return  to  the  heart 
may  also  be  produced  by  excessive  movements  of  the  thorax  as  a  re- 
sult of  artificial  respiration.  That  this  in  itself  may  cause  shock  is  known 
to  all  experimental  investigators  on  the  subject,  although  the  interpre- 
tation has  not  always  been  that  which  is  given  above.  Yandell  Hen- 
derson32 thought  that  the  excessive  ventilation  caused  a  blowing  off 
of  carbon  dioxide  from  the  blood  (see  page  293),  thus  producing  a 
low  tension  of  this  gas  in  the  blood  (acapnia),  which  he  believed  to  be 
the  responsible  factor. 

As  in  gravity  shock,  so  in  surgical  shock,  stagnation  of  blood  in  the 
splanchnic  area  is  common;  the  animal  bleeds  into  his  own  (splanchnic) 
blood  vessels  (capillaries  and  venules),  because  these  have  lost  their  tone. 
As  we  have  noted  above,  one  of  the  most  certain  ways  of  producing 
shock  is  by  exposure  and  rough  handling  of  the  abdominal  viscera.  It 
is  therefore  of  importance  to  study  the  effects  that  can  be  noted  on 
the  blood  vessels  of  this  area  under  such  conditions.  When  the  viscera 
are  first  exposed  to  air,  there  may  be  a  short  period  during  which  vaso- 
constriction is  evident.  This  is  soon  followed  by  a  dilatation  of  the 
arterioles  in  the  exposed  area,  causing  the  capillaries  and  veins  to  be- 
come markedly  distended  as  during  the  first  stage  of  inflammation.  This 
accumulation  of  blood  in  the  mesenteric  veins  has  been  shown  by  Mor- 
rison and  Hooker  to  cause  an  increase  in  the  weight  of  an  isolated  loop 
of  intestine  as  an  animal  passes  into  a  state  of  shock. 

Splanchnic  engorgement  alone  does  not,  however,  suffice  to  explain  all 
the  loss  of  blood,  and  we  are  driven  to  conclude  that  the  capillaries  of 
the  tissues  outside  the  abdomen  must  entrap  much  of  it.  As  a  matter  of 
fact,  Cannon,  and  others,  have  found  that  concentration  of  the  blood 
occurs  in  these  capillaries  as  indicated  by  comparisons  of  the  corpuscles 
and  hemoglobin  in  blood  drawn  from  veins  and  from  capillaries.  Nor- 
mally the  values  are  equal;  in  shock  the  capillary  blood  is  much  con- 
centrated. 

In  so  far  as  the  circulatory  disturbances  are  concerned,  we  may  there- 
fore sum  up  the  conditions  occurring  in  shock  as  follows:  The  blood 
accumulates  in  the  veins  and  capillaries — that  is,  in  a  part  of  the  vas- 
cular system  that  is  beyond  vasomotor  control.  The  consequent  with- 
drawal of  this  blood  from  the  circulation  produces  a  diminution  of  the 
bloodflow  in  the  vena  cava  and  consequently  an  inadequate  filling  of  the 


shock  293 

heart.  The  consequent  curtailment  in  the  systolic  discharge  does  not, 
however,  at  first  cause  any  marked  fall  of  arterial  blood  pressure  be- 
cause of  a  reciprocal  constriction  of  the  peripheral  arterioles  of  the 
body.  Meanwhile,  however,  the  stagnation  of  blood  in  the  capillary  areas  is 
progressively  increasing,  so  that  less  and  less  blood  remains  available 
for  the  systemic  circulation.  Consequently,  after  a  while,  in  spite  of 
the  arterial  constriction,  the  blood  pressure  falls  to  the  dangerous  shock 
level,  and  the  secondary  symptoms  of  fall  in  temperature,  dulling  of  the 
retlexes,  etc.,  supervene.  Increasing  viscidity  of  the  blood  also  retards 
its  flow. 

The  fundamental  question  in  the  pathogenesis  of  shock  concerns  there- 
fore the  cause  of  the  stagnation  of  circulatory  fluid  in  the  capillaries  and 
venules.  Two  hypotheses  have  been  offered,  one  being  that  the  stimulation 
of  afferent  nerve  fibers  to  the  respiratory  center  causes  excessive  alveolar 
ventilation  with  a  consequent  washing  out  of  carbon  dioxide  from  the 
blood  (acapnia),  which  causes  a  veno-capillary  atonia,  and  the  other, 
that  a  bombardment  of  the  vasoconstrictor  and  other  nerve  centers 
by  afferent  impulses  brings  these  centers  into  a  condition  of  exhaus- 
tion, which  is  the  essential  cause  of  shock.  The  acapnia  hypoth- 
esis may  be  at  once  dismissed,  since,  on  the  one  hand,  it  has  been 
shown  that  in  typical  shock  there  is  no  deficiency  of  carbon  dioxide  in 
the  venous  blood  (Short),33  and  on  the  other  hand,  conditions  of  shock 
arc  often  produced  without  excessive  breathing. 

Nor  is  there  any  evidence  to  support  the  view  that  shock  is  caused  by 
fatigue  of  the  cardinal  centers  as  a  result  of  excessive  sensory  stimu- 
lation. In  the  first  place,  it  has  been  shown  by  Mann34  that  during  han- 
dling of  the  abdominal  viscera  the  nervous  impulses  transmitted  up  the 
spinal  cord  are  much  less  marked  than  those  transmitted  when  the  cen- 
tral ends  of  sensory  nerves  are  stimulated  by  operative  processes  on  the 
limbs  and  joints,  although  shock  is  much  more  readily  produced  by  the 
former  procedure.  The  method  employed  by  Mann  for  detecting  the 
existence  of  these  afferent  impulses  was  that  of  Forbes  and  Miller,  in 
which  electrodes  are  placed  on  the  brain  stem  in  decerebrate  animals, 
and  the  current  of  action  which  accompanies  the  passage  of  nerve  im- 
pulses registered  by  a  string  galvanometer.  Although  this  method  is 
simple  and  direct  in  principle,  it  has  been  found  by  Mann  to  require 
great  care  in  practice  because  of  the  fact  that  the  slightest  movement 
of  the  head  end  of  the  animal  produces  deflections  of  the  galvanometer. 
If  the  further  results  of  this  investigation  should  show,  as  the  early 
ones  have  done,  that  shock  may  be  produced  in  an  animal  without  any 
observed  deflection  of  the  galvanometer,  it  will  disprove  once  and  for  all 


291  THE    CIRCULATION    OF    THE    BLOOD 

the  theory  that   shuck   is  dependent  upon  an   impairment   of  a   higher 
nerve  mechanism  as  a  result  of  overstimulation  by  afferent  impulses. 

Cannon35  has  recently  suggested  that  the  engorgement  of  the  splanch- 
nic blood  vessels  may  be  the  result  of  a  constriction  of  the  portal  rad- 
icles in  the  liver,  which  dams  back  the  blood  in  the  portal  circulation. 
He  points  out  that  these  radicles  have  vasoconstrictor  nerve  fibers,  as 
evidenced  by  the  fact  that  the  rate  of  flow  of  fluid  through  the  per- 
fused liver  decreases  during  asphyxia,  as  well  as  when  the  hepatic 
nerve  plexus  is  stimulated  electrically  or  when  epinephrine  is  injected 
into  the  portal  vein.  He  argues  that,  since  the  blood  vessels  in  other 
areas  of  the  body  are  constricted  in  shock,  so  also  will  be  those  of  the 
liver,  with  the  result  that  the  blood  of  the  portal  vein,  in  which  ordinarily 
there  is  a  very  low  blood  pressure  (10  mm.IIg),  will  become  dammed 
back  in  these  veins  and  therefore  removed  from  the  systemic  circulation. 
It  does  not  seem  to  the  writer,  however,  that  this  explanation  is  likely 
to  be  the  correct  one,  for,  although  it  is  true  that  vasoconstrictor  in- 
fluences have  been  shown  to  exist  in  the  hepatic  radicles  of  the  portal  vein, 
yet,  since  it  is  only  under  special  experimental  conditions  that  this  can 
be  done,  they  must  be  very  feeble  in  nature.  As  we  have  seen  else- 
where, portal  vasoconstriction  can  not  be  demonstrated  by  stimulation 
of  the  hepatic  plexus  with  stimuli  which  are  sufficient  to  produce  marked 
constriction  of  the  hepatic  artery  radicles  (see  page  255). 

The  engorgement  of  the  splanchnic  capillaries  and  venules  is  much 
more  likely  to  be  dependent  upon  local  influences  acting  on  tlie  vessels 
themselves.  "When  shock  is  produced  by  manipulation  of  the  abdominal 
viscera,  it  is  easy  to  see  how  this  local  disturbance  might  be  set  up. 
AVhen  shock  is  caused  in  other  ways,  as  by  violent  stimulation  of  sen- 
sory nerves,  the  atony  of  the  splanchnic  vessels  is  not  so  easily  accounted 
for  unless  we  assume  that  it  is  a  type  of  abnormal  reciprocal  vascular 
innervation.  For  example,  when  stimuli  are  applied  locally  to  sensory 
surfaces  under  ordinary  conditions,  a  distribution  of  the  blood  of  the 
body  takes  place,  more  being  sent  to  the  irritated  region  and  less  to 
other  parts  of  the  body  (see  page  238).  During  the  sensory  stimula- 
tion preceding  shock,  it  is  conceivable  that  this  reciprocal  innervation 
acts  in  a  faulty  manner,  causing  at  first  a  dilatation  of  the  splanchnic 
arterioles  and  thus  allowing  more  blood  to  enter  the  splanchnic  capil- 
laries and  venules,  which  being  possessed  of  little  tone  are  incapable 
of  responding  by  increased  tonicity,  so  that  they  become  overdistended 
and  the  blood  in  them  stagnates. 

In  any  case  there  is  no  doubt  that  the  initial  change  is  the  stagnation 
of  blood  in  these  vessels,  and  when  once  such  stagnation  has  occurred, 
the  process  goes  on  spontaneously  probably  on  account  of  the  accumula- 


shock  295 

1  ion  in  the  stagnant  blood  of  incompletely  oxidized  metabolic  products, 
which  raise  the  hydrogen-ion  concentration  of  the  blood,  and  produce 
a  further  relaxation  of  the  muscle  fibers  in  the  vessel  walls.  That  acid 
has  such  an  effeel  is  well  known  (page  937).  Dilatation  or  atonieity  thus 
progressively  increases  and  is  meanwhile  further  encouraged  by  the  de- 
privation of  oxygen,  for  it  has  been  shown  thai  isolated  artery  strips  do 
not  exhibit   their  usual  tonicity  "when  deprived  of  oxygen. 

Treatment 

Whatever    may    be    the    cause    of    the    atony    of   the    capillaries    and 

venules  in  shock,  the  existence  of  this  condition  indicates  that  the  most 
hopeful  line  of  treatment  is  to  cause  the  vessels  to  reacquire  their  tone. 
It  will  be  remembered  that  in  gravity  shock  in  a  rabbit  recovery  may 
be  accomplished  by  the  application  of  a  tight  binder  to  the  abdomen, 
or  by  placing  the  animal  in  a  head-down  position.  Such  measures  ap- 
plied in  the  case  of  man  have  not,  however,  been  found  of  much  value. 
Pressure  thus  applied  is  evidently  not  brought  to  bear  sufficiently  on" 
the  atonic  vessels.  Cannon  has  therefore  made  the  interesting  suggestion 
that  a  hopeful  procedure  may  consist  in  injecting  directly  into  the  ab- 
domen a  saline  solution  containing  pituitrin,  a  hormone  which,  it  will 
be  remembered,  acts  directly  on  involuntary  muscle  fiber. 

Two  other  methods  have  been  advocated  for  the  treatment  of  shock — 
namely,  saline  or  blood  transfusion  and  injection  of  epinephrine ;  but 
neither  method  has  proved  of  practical  value.  Epinephrine  injections 
do  indeed  temporarily  raise  the  arterial  blood  pressure,  but  the  subse- 
quent condition  of  shock  is  possibly  worse  than  that  originally  present. 
After  the  injection  of  blood  or  saline  solution  containing  gelatin  or 
mucilage,  the  blood  pressure,  although  temporarily  raised,  very  quickly 
falls  again.  In  this  regard  surgical  shock  differs  from  the  shock  follow- 
ing severe  hemorrhage,  in  which,  as  explained  elsewhere,  recovery  of  the 
blood  pressure  as  well  as  of  the  general  condition  of  the  animal  can 
be  accomplished  by  transfusion  with  blood  or  with  saline  solution  con- 
taining mucilage  or  gelatin.  This  would  indicate  that  there  is  some 
essential  difference  between  these  two  forms  of  shock  (see  page  140). 
The  only  treatment  of  avail  appears  to  be  to  keep  the  patient  warm  and 
to  remove  causes  of  excessive  pain. 

Causes  of  Secondary  Symptoms 

It  remains  to  consider  the  cause  of  some  of  the  secondary  conditions 
developing  in  shock — namely,  the  disturbances  in  sensation  and  motion 
and  the  fall  in  body  temperature.    All  of  these  are  undoubtedly  depend- 


296  THE    CIRCULATION   OF    THE   BLOOD 

ent  upon  the  low  arterial  blood  pressure,  although  some  authors  have 
suggested  that  the  loss  of  sensation  may  be  dependent  upon  an  increased 
resistance  or  block  at  the  synapses  of  the  receptor  neurons  (page  803). 
This  suggestion  depends  on  the  fact,  demonstrated  by  Sherrington,  that 
repeated  stimulation  of  the  receptors  of  a  reflex  arc  produces  fatigue 
of  that  particular  reflex,  and  that  this  fatigue  must  be  resident  in  the 
synapsis  and  not  in  the  motor  neuron,  since  the  same  motor  neuron 
that  participated  in  the  fatigue  can  still  be  called  into  activity  by  afferent 
stimuli  transmitted  to  its  nerve  cell  through  other  sensory  pathways 
(see  page  825).  It  is  thought  that  in  shock  the  frequent  afferent  stimula- 
tion produces  synaptic  fatigue  and  therefore  dulls  the  sensory  responses 
of  the  animal.  The  researches  of  Mann  above  referred  to,  in  which  he 
shows  that  shock  may  occur  without  any  demonstrable  afferent  stimuli 
in  the  brain  stem,  would  seem,  however,  to  negative  the  above  hypothesis. 

The  raised  threshold  of  sensory  stimulation  is  no  doubt  an  effect  of  the 
low  blood  pressure.  It  has  been  shown,  for  example,  by  E.  L.  Porter36 
that  when  the  arterial  blood  pressure  is  maintained  at  a  uniform  level, 
the  threshold  stimulus  for  spinal  cord  reflexes  remains  practically  uni- 
form, but  becomes  promptly  increased  when  the  arterial  blood  pressure 
is  made  to  fall.  Why  a  lower  blood  pressure  should  have  this  effect  is, 
however,  difficult  to  understand  in  the  light  of  the  researches  of  Stewart 
and  his  coworkers,  Avho,  as  remarked  above,  found  that  the  cells  of  the 
central  nervous  system  may  endure  total  anemia  for  many  minutes  and 
still  recover  their  physiologic  condition.  It  may  be,  however,  that  the 
low  blood  pressure  affects  the  conductivity  of  the  synapsis. 

The  muscular  weakness  is  probably  also  dependent  on  low  blood 
pressure,  for  it  has  been  found  in  animals  that,  when  the  arterial  blood 
pressure  is  lowered  to  about  90  mm.  Hg.  the  muscles  contract  much  less 
efficiently  than  ordinarily.  The  fall  in  body  temperature  is  dependent 
upon  the  muscular  inefficiency. 

In  conclusion,  it  should  be  pointed  out  that  W.  T.  Porter,  in  the  inves- 
tigation of  acute  shock  met  with  at  the  front,  has  found  that,  in  many 
cases  at  least,  the  circulatory  disturbance  is  due  to  a  condition  of  fat 
embolism.  The  fat  is  derived  from  the  marrow  of  long  bones,  such  as 
the  femur,  by  injuries  which  smash  the  bones.  Porter's  observations 
are  at  least  very  suggestive. 

CIRCULATION  REFERENCES 

(Monographs) 

Winers,  C.  J.:     The  Circulation  in  Health  and  Disease,  Philadelphia,   1015. 
Mackenzie,  J.:     Diseases  of  the  Heart,  Oxford  Medical  Publishers,  ed.  2,  1910. 
Lewis,    Thomas:     Mechanism   of    the    Heart    Beat,    1911,    Shaw   &    Son,    Fetter   Lane, 
London. 


SHOCK 


297 


Lewis,  Thomas:     Harvey  Lectures,  1913-1914,  J.  B.  Lippineott  Co. 

Lewis,  Thomas:     Clinical  Disorders  of  the  Beart  Beat,  P.  B.  Iloeber,  New  York,  1912. 

Hill.     Leonard:     The    Mechanism    of    the    Circulation    of    the    Blood,    in    Schafer's 

Physiology,  ii,  1900.    Young  J.  Pentland. 
Qaskell    W.    H.:     The   Contraction    of    Cardiac    Muscle,    in    Schafer's    Physiology,    u, 

1900,  Young  J.  Pentland. 
Flack,  M.:     Further  Advances  in  Physiology,  1909.     Ed.  by  Leonard  Hill,  E.  Arnold, 

London. 
Porter,  W.  T.:     American  Text  Book  of  Physiology,  W.  B.  Saunders  Co.,  1900. 

(Original  Papers) 

iMacWilliam,  J.  A.,  et  al:     Heart,   1913,  iv,  393;   ibid.,    1914,  v,  153;   Brit.  Med. 
Journal,  Nov.,  1914;   VII  Internat.  Congress   of  Medicine,  London,   1913,  Sec. 
II,  Phvsiology. 
2Hill,  Leonard,  F.  R.  S.,  et  al.:     Proc.  Roy.  Soc,  1914,  B,  lxxxvii,  344;  ibid.,  1915,  B, 

lxxxviii,  508  and  516. 
sErlanger,  J.:     Am.  Jour.  Physiol.,  1916,  xxxix,  401;  ibid.,  1916,  xl,  82. 
4Downs,  A.  W.:     Am.  Jour.  Physiol.,  1916,  xl,  522. 
sBayliss,  W.  M.:     Proc.  Roy.  Soc,  1916,  lxxxix,  B,  380. 
eKnowlton,  F.  P.:     Jour.  Physiol.,  1911,  xliii,  219. 
?Milroy,  T.  H.:     Jour.  Physiol.,  1917,  li,  259. 
sEyster  and  Meek:     Heart,  1914,  v,  119;  ibid.,  194,  v,  137;  Am.  Jour.  Physiol.,  1914, 

xxxiv,  368. 
aPorter,  W.  T.:     Art.  on  Circulation  in  an  American  Textbook  of  Physiology,  W.  B. 
Saunders  Co.,  1900. 
"Brodie,  T.  G.:     Proc.  Physiol.  Soc,  1905,  Jour.  Physiol.,  1905,  xxxii. 
"Stewart,  G.  N.:     Heart,  1911,  iii,  33. 
izGarrey,  W.:    Am.  Jour.  Physiol.,  1912,  xxx,  451. 
"Mines,  G.  R. :     Jour.  Physiol.,  1913,  xlvi,  188. 
"Cohn,  A.  E.:     Jour.  Exper.  Med.,  1912,  xvi,  732;  Robinson,  G.  Canby:     Ibid.,  1913, 

xvii,  429;  Cohn  and  Lewis,  T.:     Ibid.,  1913,  xviii,  739. 
"Mathison,  G.  C:     Jour.  Physiol.,  1910,  xli,  416. 

icPorter,  W.  T.:     Am.  Jour.  Physiol.,  1911,  xxvii,  276;  ibid.,  1915,  xxxvi,  418. 
"Martin,  E.  G.,  and  co-workers:     Am.  Jour.  Physiol.,  1914,  xxxii,  212;   xxxiv,   220; 

1915,  xxxviii,  98;  1916,  xl,  195. 
"Bayliss,  W.  M.:     Proc  Roy.  Soc,  1908,  lxxx,  B,  339. 
"Hill,  Leonard:     The  Physiology  and  Pathology  of  the  Cerebral  Circulation,  J.  and 

A.  Churchill,  1896. ' 
zoHill,  L.,  and  Macleod,  J.  J.  R.:     Jour.  Physiol.,  1900,  xxvi,  394. 
siMacleod,  and  Pearce,  R.  G.:     Am.  Jour.  Physiol.,  1914,  xxxv,  87. 
22Porter,  W.  T.:     Am.  Jour.  Physiol.,  1898,  i,  144. 
23Hill,  L.,  and  Barnard,  H.:     Jour.  Physiol.,  1887,  xxi,  323. 
"Carter,  E.  P.:     Jour.  Lab.  and  Clin.  Med.,  1916,  i,  719. 

zsElliot-Smith,  G.,  and  Pear,  T.  H.:     Shell  Shock,  Longmans,  Green  &  Co.,  1917. 
26Porter,  W.  T.:    Am.  Jour.  Physiol.,  1907,  xx,  399. 
27Seelig,  M.  G.,  and  Joseph,  D.  R.:     Jour.  Lab.  and  Clin.  Med.,  1916,  i,  283;  also  See- 

lig  and  Lyon,  E.  P.:     Surg.,  Gynec,  and  Obst,,  1910,  ii,  146. 
28Henderson,  Yandell:    Am.   Jour.  Physiol.,   1908,  xxi,   155;    also   Mann:     Bull.   Johns 
Hopkins  Hosp.,  1914,  p.  210;  Markwald,  J.,  and  Starling,  E.  P.:  Jour.  Physiol., 
1913,  xlvii,  275. 
29Morrison,  R,  A.,  and  Hooker,  D.  R.:     Am.  Jour.  Physiol.,  1915,  xxxvii,  86. 
sopike,  F.  H.,  Stewart,  G.  N.,  and  Guthrie,  C.  C:     Jour.  Exper.  Med.,  1908,  x,  499; 

see  also  Dollev,  D.  H.:     Jour.  Med.  Research,  1909,  p.  95,  and  1910,  p.  331. 
siJanewav,  H.  H.,  and  Jackson,  H.  C:     Proc.  Soc.  Exper.  Biol,  and  Med.,  1915,  xn, 
193;  Erlanger,  J.:     Gesell,  Gasser,  Proc  Am.  Physiol.  Soc,  Am.  Jour.  Physiol., 
1918,  xlv. 


298  THE    CIRCULATION     OF    THE    BLOOD 

32Heudcrson,  Y.,  and  Haggard,  W.  H.:     Jour.  Biol.  Chcm.,  1918,  xxxiii,  333,  345-355- 

3G5  (gives  older  references).     See  also  Macleod,  J.  J.  K.:     Jour.  Lab.  and  Clin. 

Med.,  (editorial),  1918,  iii. 
33Short,  Rendel:    Lancet,  London,  1914,  p.  131; 
34Maiin:     Jour.  Am.  Med.  Assn.,  1918,  lxx,  (511.     Also  Boston   Med.  and  Surg.  Jour., 

1917. 
ssCannon,  W.  B.:     Papers  by  Cannon  and  Collaborators  in  Jour.  Am.  Med.  Assn.,  1918, 

lxx,  520,  526,  531,  611,  618. 
sePorter,  E.  L.:     Proc.  Am.  Physiol.  Soc,  Am.  Jour.  Physiol.,  1916,  xlii,  606. 
37Wiggers,  C.  J.,  and  Dean,  A.  L.:     Am.  Jour.  Physiol.,   1916,  xlii,  476;   Am.  Jour. 

Med.  Sc,  1917,  clii,  666. 


PART  IV 
THE   RESPIRATION 


CHAPTER  XXXIV 
RESPIRATION 

For  convenience,  the  physiology  of  respiration  may  be  considered  un- 
der its  mechanics,  its  control,  and  its  chemistry. 

THE  MECHANICS  OF  RESPIRATION 

Of  the  many  factors  concerned  in  maintaining  the  normal  functioning 
of  the  animal  body,  the  respiratory  act  is  probably  the  most  important. 
On  this  account  and  also  because  we  are  conscious  of  the  respiratory 
movements,  the  physiology  of  respiration  has  been  studied  from  the 
earliest  times.  Much  of  the  earlier  work  naturally  concerned  itself 
with  the  study  of  the  air  that  enters  and  leaves  the  lungs  at  each  respi- 
ration— the  ventilation  of  the  lungs,  as  it  may  be  called.  Two  obvious 
properties  of  the  respired  air  are:  (1)  its  pressure  and  (2)  its  volume. 

The  Pressure  of  the  Air  in  the  Respiratory  Passages — the  Pulmonary 
or  Intrapulmonic  Pressure 

This  is  readily  measured  by  inserting  a  tube  into  one  nostril  and  con- 
necting the  tube  with  a  manometer;  at  each  normal  inspiration  the 
manometer  registers  a  negative  pressure  of  2  or  3  mm.  Hg,  and  at  each 
expiration,  a  positive  pressure  of  about  the  same  degree.  Although 
normally  of  small  magnitude,  the  intrapulmonic  pressure  may  become 
very  great  when  any  obstruction  is  offered  to  the  free  passage  of  the 
air.  The  greatest  possible  expiratory  pressure  can  be  measured  by  sim- 
ply blowing  into  a  mercury  manometer,  when  it  will  be  equal  to  that 
which  all  the  muscles  of  the  thorax  and  abdomen  can  exert  in  compress- 
ing the  lungs.  In  a  strong  man  it  may  amount  to  more  than  100  mm. 
Hg.  Similarly,  the  greatest  possible  negative  pressure  on  inspiration 
may  be  measured  by  attempting  to  inspire  through  a  tube  connected 
with  a  manometer.    It  represents  the  force  with  which  the  musculature 

299 


300  THE   RESPIRATION 

of  the  thorax  and  abdomen  can  open  up  the  thoracic  cage,  and  may 
equal  -70  mm.  Hg.  These  measurements  in  themselves  are  not  of  much 
importance,  except  as  a  measure  of  muscular  development. 

Intrapulmonic  pressures  that  are  intermediate  between  the  two  ex- 
tremes will  be  acquired  in  the  lower  air  passages  in  cases  in  which  there 
is  partial  obstruction  of  the  upper  respiratory  passages,  as  in  bronchitis, 
spasm  of  the  glottis,  diphtheria,  etc.  During  coughing  also,  the  intra- 
pulmonic pressure  may  become  very  high.  In  this  act  the  thorax  is  first 
filled  with  air  by  a  deep  inspiration;  the  glottis  is  then  closed,  and  a 
forced  expiration  is  made.  When  a  sufficiently  high  intrapulmonic  pres- 
sure is  attained,  the  glottis  opens  and  the  sudden  change  in  pressure 
causes  so  forcible  a  blast  of  air  that  the  offending  foreign  substance  is 
frequently  carried  with  it  out  of  the  air  passages.  It  is  often  assumed 
that  during  coughing  the  sudden  increase  in  pressure  in  the  alveoli  will 
tend  to  cause  their  walls  to  rupture.  This,  however,  is  not  the  case. 
The  alveoli  do  not  alone  support  the  increase  of  pressure;  they  merely 
act  as  the'  inner  layer  of  a  practically  homogeneous  structure  com- 
posed of  lung,  pleura  and  thoracic  cage.  When  the  tissues  of  the  lung 
are  partially  degenerated  or  atrophied,  as  in  old  people,  then  it  is  pos- 
sible that  a  rupture  may  take  place,  but  under  ordinary  conditions  it 
is  not  likely  to  occur. 

Amount  of  Air  in  the  Lungs 

Measurements  of  the  amount  of  respired  air  have  recently  assumed  a 
considerable  interest  on  account  of  the  various  applications  which  can 
be  made  of  them  in  the  study  of  lung  conditions.  The  tidal  air  is  that 
which  enters  and  leaves  the  lungs  with  each  respiration  (about  500  c.c.)  ; 
the  complement al  air  is  that  which  we  can  take  in  over  and  above  an 
ordinary  tidal  respiration  (about  1500  c.c.)  ;  and  the  supplemental  air, 
is  that  which  we  can  give  out  after  an  ordinary  tidal  expiration  (about 
1500  c.c).  Taking  these  three  together,  we  have  what  is  known  as  the 
vital  capacity.  It  is  usually  about  3500  c.c,  and  is  represented  by  the 
amount  of  air  which  Ave  can  expel  from  the  lungs  after  as  deep  an  inspi- 
ration as  possible.  The  vital  capacity  is  diminished  in  certain  pulmo- 
nary diseases  (see  page  314).  After  all  the  supplemental  air  has  been 
expelled,  there  still  remains  in  the  lungs  a  large  volume  of  air  which 
can  not  be  voluntarily  expelled.  This  is  known  as  the  residual  air.  To 
measure  it  in  a  dead  animal  it  is  necessary  to  clamp  the  trachea,  open 
the  thorax,  remove  the  lungs  to  a  vessel  of  Avater,  and  then  allow  the  air 
to  collect  from  the  opened  trachea  in  an  inverted  graduated  cylinder. 
One  part  of  the  residual  air  is  sometimes  called  the  minimal  air;  it  is 


RESPIRATION 


301 


represented  by  thai  which  is  not  expelled  from  the  Lungs  of  a  dead 
animal  when  the  thorax  is  opened.  In  the  collapse  of  the  lungs  thus 
produced,  the  alveoli  are  not  completely  emptied  of  air,  because  some 
becomes  pocketed  within  them  and  is  expelled  only  when  the  lungs  are 
compressed  under  water. 

The  volume  of  the  residual  air  can  readily  be  measured  during  life 
by  causing  a  person,  after  a  forced  expiration,  to  take  two  or  three 
breaths  in  and  out  of  a  rubber  bag  containing  a  measured  quantity  of 
an  indifferent  gas  such  as  hydrogen.  Suppose  the  bag  to  contain  at 
the  start  4000  c.c.  of  hydrogen,  and  after  a  few  breaths  3000  c.c.  of 
this  gas  and  1000  c.c.  of  other  gases  (the  total  volume  of  hydrogen  and 
expired  air  in  the  bag  being  still  4000  c.c);  then  the  residual  air  will 


Maximum  inspiration-/ 


Complemental  air . 


Ordinary  inspiration 

TIDAL  AIR- 
Ordinary  expiration  — 


Supplemental  ai)  ■ 

Maximum  expiration  ■ 

H >.«/ dual  air 


2000  120 

c  c        cub.  in 


500  c.c.  or  jo  cut.  in 


150O       100il 
*  or     V:  := 

l  c.c-      cuv,m 


\  Vital  capacity 


Capacity  of  equilibrium 


Fig.    107. — Amounts    of   air   contained   by   the   lungs   in   various   phases   of   ordinary    and    of    forced 

respiration.      (From   Waller.) 


be  1333  c.c,  for  it  is  evident  that  after  a  few  breaths  the  composition  of 
the  expired  air  in  the  bag  will  be  the  same  as  that  in  the  lungs.  This 
calculation  is  based  upon  the  assumption  that  no  hydrogen  is  absorbed 
by  the  blood  during  the  experiment,  which  is  not  strietly  the  case. 
The  amount  absorbed  is,  however,  so  small  in  two  or  three  breaths  as  to 
make  it  permissible  to  disregard  it.  The  measurement  can  also  be  made 
by  taking  a  few  breaths  in  and  out  of  a  bag  containing  pure  02.  By 
ascertaining  the  proportion  of  nitrogen  that  collects  in  the  bag,  the 
quantity  of  residual  air  can  be  calculated.  We  shall  see  later  that  the 
measurement  of  the  residual  air  during  life  has  some  practical  impor- 
tance in  connection  with  the  measurement  of  the  bloodflow  through  the 
lungs. 


302  THE    RESPIRATION 

Alveolar  and  Dead  Space  Air 

In  addition  to  these  moieties  of  respired  air,  we  have  to  consider  the 
division  of  the  air  in  the  lungs  into  what  is  called  alveolar  air  and 
dead-space  air.  The  former  is  the  air  which  comes  in  contact  with  the 
epithelium  through  which  gas  diffusion  between  the  blood  and  the  air 
occurs,  the  latter  being  the  air  which  fills  the  respiratory  passages.  The 
dead  space  can  not  be  defined  anatomically  with  exactitude ;  it  is  func- 
tional rather  than  morphologic. 

Measurement  of  the  volume  of  the  alveolar  and  dead-space  air  can  be 
made  in  an  animal  breathing  under  normal  conditions  by  taking  ad- 
vantage of  the  fact  that,  while  it  is  in  the  lungs,  the  air  has  added  to 
it  C02  gas,  which  is  present  in  the  inspired  air  only  in  negligible  traces. 
The  necessary  data  are:  (1)  the  volume  of  the  tidal  respiration;  (2)  the 
percentage  of  C02  in  alveolar  air;  (3)  the  percentage  of  C02  in  the  tidal 
air.     Suppose  the  values  to  be  500  c.c,  6  per  cent  and  4  per  cent,  re- 

4 
spectively;  then  the^ volume  of  alveolar  air  must  be  500  x-^  =  333  c.c, 

and  the  dead  space  167  c.c.  The  measurement  so  made  is  accurate  only 
when  certain  precautions  are  taken.  Because  of  the  practical  impor- 
tance of  this  part  of  our  subject  we  shall,  however,  defer  its  further 
consideration  until  we  have  become  familiar  with  the  general  features 
of  pulmonary  physiology.  Since  the  first  air  1o  move  into  the  alveoli 
at  the  beginning  of  inspiration  is  that  present  in  the  dead  space, — the 
last  air  expelled  from  the  alveoli  on  the  previous  expiration, — it  is  of 
no  value  in  purifying  the  air  already  present  in  the  alveoli.  If  we  take 
a  tidal  inspiration  as  amounting  to  500  c.c.  and  the  functional  dead  space 
as  150  c.c,  it  is  plain  that  only  350  c.c.  of  the  outside  air  gains  the 
alveoli,  and  that  the  subsequent  expiration  is  composed  of  150  c.c  of 
outside  air  that  had  lodged  in  the  dead  space  plus  350  c.c.  of  alveolar  air. 

These  facts  deserve  a  certain  amount  of  emphasis  because  of  their 
practical  importance  in  many  phenomena  connected  with  respiration. 
One  seldom  thinks,  for  example,  that  out  of  the  500  c.c  of  air  inspired 
with  each  breath,  only  350  c.c  reaches  the  alveoli,  where  it  comes  in 
contact  with  the  2500-3000  c.c  of  air  already  present  in  this  part  of  the 
lungs. 

There  must  therefore  be  a  sort  of  interface  somewhere  in  the  alveoli 
between  the  fresh  outside  air  that  comes  in  with  each  breath  through 
the  bronchioles  and  the  air  which  is  more  or  less  stagnant  in  the  alveoli. 
This  interface  must  move  backward  and  forward  somewhat  with  each 
breath,   and   a  rapid   diffusion   of  oxygen   and  of  C02  must  take  place 


RESPIRATION  303 

across  it  between  the  inspired  air  and  thai  in  the  alveoli.    It  is  impossible 
to  fix  any  anatomic  point  at  which  the  interface  occurs. 

The  above  described  mechanism  for  the  ventilation  of  the  alveoli  in- 
sures the  maintenance  of  slight  bu1  constant  ehanges  in  the  composition 
of  the  air  next  the  alveolar  epithelium.  It  helps  to  prevent  sudden  varia- 
tions in  the  amount  of  gases  in  the  blood,  particularly  of  C02.  Should 
such  variations  occur,  irregular  stimulation  of  the  respiratory  and  other 
important  centers  that  are  influenced  by  the  amount  of  this  gas  present 
in  simple  solution  in  the  blood,  Mould  be  the  result.  The  mechanism 
serves  as  a  sort  of  mechanical  buffer  by  diminishing  the  sudden  changes 
in  gas  concentration  produced  by  inspiration  and  expiration. 

Respiratory  Tracings 

The  measurements  of  air  for  the  determination  of  the  foregoing  val- 
ues are  made  by  the  use  of  meters  of  various  types.  Sometimes,  how- 
ever, it  is  necessary  to  obtain  an  inscribed  record  of  the  respirations. 


Fig.    108. — Pneumograph.      The    straps    (h,    b)    are    held    around    the    thorax,    and    the    tube    of    the 
tambour    connected    by    rubber    tubing    with    a    recording    tambour. 

This  may  be  either  qualitative  or  quantitative.  A  qualitative  record  is 
taken  by  attaching  some  sort  of  receiving  tambour  to  the  thoracic  "wall 
(the  best  type  is  shown  in  Fig.  108),  and  connecting  this  with  a  record- 
ing tambour  arranged  to  write  on  a  blackened  surface.  When  it  is 
desired  merely  to  count  the  respirations  or  to  observe  their  regularity, 
such  a  tracing  is  all  that  is  required,  but  obviously  it  does  not  tell  us 
how  much  air  has  entered  and  left  the  lungs  at  each  respiration.  To 
obtain  a  quantitative  tracing,  Ave  must  either  connect  a  recording  instru- 
ment with  the  trachea  or  inclose  the  body  of  the  animal  in  what  is 
known  as  a  body  plethysmograph.  '  In  observations  on  laboratory  an- 
imals the  best  type  of  recording  instrument  to  connect  with  the  respira- 
tory passages  is  the  Gad  or  Krogh  pneumograph.  A  body  plethysmograph 
as  used  in  the  case  of  man  is  shown  in  Fig.  109.  All  these  instruments 
must  of  course  be  calibrated,  which  is  done  by  pouring  a  definite  num- 


304 


THE   RESPIRATION 


ber  of  c.c.  of  water  from  a  graduate  into  a  bottle  with  which  the  record- 
ing instrument  is  connected  by  tubing.  The  displacement  of  the  writing 
point  gives  us  the  necessary  data  for  standardization. 

The  Intrapleural  Pressure 

The  air  which  Ave  have  just  been  considering  depends  for  its  move- 
ment in  and  out  of  the  air  passages  upon  changes  occurring  on  the  outer 
aspect  of  the  lungs  in  the  space  between  them  and  the  thoracic  wall. 
This  is  called  the  intrapleural  space.  It  does  not  really  exist  as  an 
actual  space  in  the  living  animal,  for  the  visceral  pleura  which  covers 
the  lungs  is  in  accurate  and  intimate  apposition  with  the  parietal  pleura 
on  the  inner  aspect  of  the  thorax. 


Fig.     109. 


-Body    plethysmograph     for     recording     respiration. 

Priestley.) 


(From    J.     S.     Haldane     and    J.     G. 


If  the  thoracic  Avails  are  punctured  in  a  liATing  animal  or  in  one  which 
has  recently  died,  the  air  will  rush  into  the  thorax,  the  two  layers 
of  pleura  separate,  and  the  lungs  collapse,  causing  temporarily  a  space 
to  be  formed  betAveen  the  tAvo  layers  of  pleura  and  indicating  that  a 
certain  subatmospheric  or  negative  pressure  must  exist  in  the  intact 
thorax  to  preA^ent  the  lungs  from  collapsing.  The  degree  of  this  nega- 
tiA-e  pressure  may  be  measured  by  connecting  a  tube  and  a  manometer 
Avith  the  thoracic  cavity.  While  the  thorax  is  at  rest,  as  in  expiration 
or  immediately  after  death,  this  pressure  amounts  to  about  -5  milli- 
meters.* On  inspiration  it  increases  to  -10  millimeters.  There  are  there- 
fore tAvo  problems  to  be  considered:  (1)  the  cause  of  the  negatiAre  pres- 
sure in  the  quiescent  thorax,  and  (2)  the  cause  of  the  increase  of  the 
negatiA-e  pressure  during  inspiration. 


*The  minus  sign  indicates  that  the  pressure  is  negative  or  subatmospheric.     It  is  a  suction  pressure. 


RESPIRATION  305 

The  Permanent  Negative  Pressure. — Let  us  start  with  the  changes 
that  occur  in  the  thorax  when  the  first  breath  is  drawn.  While  the  an- 
imal is  still  in  utero,  the  lungs  completely  fill  the  thorax.  When  the 
first  breath  is  drawn  the  thoracic  cage  expands  more  quickly  than  the 
lungs,  so  that  the  latter  become  si  retched,  the  stretching  force  being 
the  air  that  is  introduced  into  them  from  the  outside  through  the  tra- 
chea and  bronchial  tubes.  On  becoming  stretched  the  lungs  fill  the 
increased  space  created  in  the  thorax  by  the  greater  expansion  of  the 
thoracic  cage.  This  in  itself,  however,  would  not  explain  the  cause  of  a 
subatmospheric  pressure  in  the  intrapleural  space.  Another  factor  must 
come  into  play — namely,  the  elastic  tissue  of  the  lungs,  which  by  the 
expansion  will  become  stretched  and,  therefore,  tend  constantly  to  re- 
lax to  its  previous  condition  and  so  exert  a  pull  on  the  structures  be- 
tween it  and  the  thoracic  wall.  It  is  this  elastic  recoil  which  we  really 
measure  when  we  connect  a  manometer  with  the  intrapleural  space. 
Throughout  life  the  lungs  remain  of  smaller  size  than  the  thoracic  wall, 
and  therefore  to  fill  the  thoracic  cavity  they  are  constantly  more  or 
less  distended  and  the  elastic  tissue  somewhat  stretched.  The  lungs 
are,  however,  not  the  only  structures  in  the  thorax  which  become  ex- 
panded; all  thin-walled  vessels  and  viscera,  like  the  veins,  the  esopha- 
gus, the  auricles,  etc.,  must  also  become  opened  out  a  little. 

When  the  thoracic  wall  is  punctured  and  the  outside  air  allowed  free 
entry  to  the  intrapleural  space,  differences  in  pressure  no  longer  exist 
on  the  inner  and  outer  aspects  of  the  lungs,  so  that  they  collapse  into 
the  postmortem  condition  on  account  of  the  elastic  recoil.  If  a  puncture 
in  the  thoracic  wall  of  a  living  animal  is  immediately  occluded,  the 
lungs  will  expand  again,  because  the  blood  absorbs  the  gases  from  the 
intrapleural  space  and  recreates  the  partial  vacuum  required  to  expand 
the  lungs.  This  absorption  of  gas  in  the  pleural  cavity  is  usually  quite 
rapid;  but  if  the  pneumothorax,  as  the  condition  is  called,  is  allowed  to 
persist  for  any  length  of  time,  the  lungs  will  not  become  properly  ex- 
panded again. 

The  Greater  Negative  Pressure  on  Inspiration. — The  cavity  of  the  tho- 
rax becomes  increased  in  all  diameters  during  inspiration,  with  the  re- 
sult that  a  greater  space  in  the  pleural  cavity  has  to  be  filled.  All  the 
thin-Availed  structures  in  the  thorax  therefore  become  still  more  stretched, 
the  lungs  of  course  participating  to  the  greatest  extent  because  of  the 
entrance  of  outside  air.  The  stretching  of  the  elastic  structures  causes 
a  greater  pull,  or  negative  pressure,  to  be  exerted  in  the  pleural  cavity. 
Instead  of  being  -5  mm.  Hg,  as  in  expiration,  the  intrathoracic  pressure 
now  comes  to  be  above  -10  mm.  Hg. 

When  any  obstruction  exists  in  the  air  passages,  the  changes  in  intra- 


306  THE   RESPIRATION 

thoracic  pressure  produced  by  the  movements  of  respiration  become 
more  pronounced  than  under  normal  conditions.  When  the  thorax  ex- 
pands with  the  trachea  blocked,  the  lungs  are  not  able  to  open  up  suffi- 
ciently to  fill  all  the  space  so  that  there  is  excessive  dilatation  of  the 
veins,  auricles  and  esophagus,  as  well  as  drawing  in  of  the  intercostal 
spaces  and  bulging  upwards  of  the  diaphragm.  If  a  manometer  is  con- 
nected with  the  pleural  space  under  these  conditions,  a  very  large 
negative  or  suction  pressure  will  be  observed,  amounting  often  to  -70 
or  -80  mm.  Hg.  It  is  possible  that  under  such  conditions  some  space 
might  temporarily  exist  between  the  parietal  and  visceral  layers  of  the 
pleura,  but  it  could  not  remain  long,  for  it  would  very  soon  be  filled 
by  fluid  exuding  from  the  blood  vessels.  In  the  opposite  condition,  in 
which  the  respiratory  passages  are  blocked  and  a  forced  expiration  is 
made,  as  for  example  in  the  first  stage  of  coughing  or  during  such  acts 
as  defecation  and  parturition,  the  thoracic  cage  is  compressed  upon  the 
viscera,  with  the  result  that  the  air  in  the  lungs  assumes  a  positive 
pressure,  amounting  often  to  nearly  100  mm.  Hg.  If  a  puncture  wound 
is  made  in  the  thorax  under  these  conditions,  the  lungs  instead  of  col- 
lapsing will  bulge  out  of  the  wound,  for  'what  is  really  occurring  is 
that  the  thorax  is  forcibly  contracting  on  occluded  sacs  of  air. 

It  is  the  alternating  changes  in  intrapleural  pressure  that  are  respon- 
sible for  the  changes  in  intrapulmonic  pressure  and  these  for  the  move- 
ment of  air  in  and  out  of  the  lungs  with  each  respiration.  In  other 
words,  the  thorax  does  not  expand  on  inspiration  because  air  rushes 
in,  as  the  uninitiated  imagine,  but  air  rushes  in  because  the  thorax 
expands. 

The  Influence  of  Intrapleural  Pressure  on  the  Blood  Pressure. — The 
movements  of  respiration  produce  effects  on  the  vascular  system  that 
are  of  considerable  importance  in  maintaining  the  circulation  of  the 
blood.  If  an  arterial  blood-pressure  tracing  is  examined,  it  will  be 
observed  that  aside  from  the  cardiac  pulsations  large  waves  exist  on  it  that 
are  approximately  synchronous  with  the  respiratory  movements,  the 
upstroke  of  each  of  these  waves  corresponding  in  general  with  inspira- 
tion, and  the  downstroke  with  expiration  (Fig.  22).  These  respiratory 
variations  in  blood  pressure  might  be  due  either  to  changes  in  heart 
rhythm  or  to  a  purely  mechanical  cause.  Regarding  the  first  possi- 
bility, it  is  indeed  the  case  in  most  animals  that  the  pulse  is  quicker  on 
inspiration  than  on  expiration,  but  that  this  alone  is  not  an  adequate 
explanation  of  the  rise  is  shown  by  the  fact  that  it  still  persists  after 
the  vagus  control  of  the  heart  has  been  eliminated,  either  by  cutting 
the  nerve  or  by  the  action  of  atropine. 

The  cause  must  therefore  be  a  mechanical  one.     Bearing  in  mind  the 


RESPIRATION  307 

effects  which  we  have  scon  arc  produced  on  the  movement  of  air  in  and 
out  of  the  Lungs  by  the  changes  in  capacity  of  the  thorax  with  each  res- 
piration, "\ve  naturally  assume  that  the  increase  in  blood  pressure  may 
be  due  to  the  fact  that  on  inspiration  more  blood  is  sucked  out  of  the 
systemic  veins  into  those  of  the  thorax,  that  this  excess  when  it  is  pro- 
pelled by  the  heart  into  the  arteries  raises  the  blood  pressure,  and  that 
on  expiration  the  opposite  condition  obtains.  That  the  movements  of 
the  thorax  on  inspiration  do  accelerate  the  speed  with  which  the  venous 
blood  is  traveling  towards  the  heart  can  easily  be  shown  by  measure- 
ments of  bloodflow. 

This  explanation,  however,  does  not  suffice  to  account  for  all  the 
changes  of  blood  pressure  which  occur  in  respiration,  for  if  we  take 
very  accurate  tracings  of  blood  pressure  and  of  the  respiratory  move- 
ments side  by  side,  we  shall  find  that,  although,  in  general,  the  blood 
pressure  rises  with  inspiration,  yet  the  beginning  of  the  rise  is  consid- 
erably delayed;  that  is,  immediately  following  the  beginning  of  the 
inspiratory  act  the  arterial  blood  pressure  continues  for  some  time  to 
fall,  and  at  the  beginning  of  expiration  it  continues  for  some  time  to 
rise  (Fig.  22).  Moreover,  it  will  be  found,  if  tracings  taken  from  dif- 
ferent animals  are  compared,  that  frequently  the  general  effect  of  ex- 
piration is  to  cause  more  rise  than  fall,  and  of  inspiration  more  fall 
than  rise.  It  will  be  found  that  these  differences  are  dependent  largely 
on  the  type  of  respiration,  whether  thoracic  or  abdominal  (Lewis).11 

Let  us  consider  first  of  all  exactly  what  will  happen  in  an  animal 
breathing  entirely  by  the  thorax  (e.g.,  the  rabbit).  The  first  effect  of 
the  inspiration  is  to  cause  the  veins  leading  to  the  auricles,  the  auricles 
themselves  and  the  blood  vessels  of  the  lungs  to  become  suddenly  ex- 
panded. More  blood  therefore  will  flow  into  them.  For  a  moment  or 
two  this  blood  will,  however,  tend  to  stagnate  in  the  more  capacious 
vessels,  and  it  will  be  some  time  until  it  finds  its  way  to  the  left  side 
of  the  heart;  therefore  the  initial  effect  of  inspiration  is  a  distinct  fall 
in  arterial  blood  pressure.  When  the  extra  space  created  in  the  blood 
vessels  has  been  filled  with  blood, — that  is,  when  inspiration  has  prac- 
tically ceased, — the  blood  will  flow  on  in  increased  volume  to  the  left 
side  of  the  heart,  and,  therefore,  raise  the  arterial  blood  pressure.  On 
expiration  the  first  effect  is  that  the  diminishing  negative  pressure  will 
cause  the  thin-walled  vessels  mentioned  above  to  constrict  and  thus 
squeeze  the  blood  inside  them  into  the  left  side  of  the  heart  and  raise 
the  pressure ;  but  the  ultimate  effect  in  the  later  stages  of  expiration 
will  be  that  the  vessels,  being  constricted,  will  allow  less  blood  through 
them  and  the  arterial  blood  pressure  will  fall. 

Take  now  the  ease  of  abdominal  respiration.     In  inspiration  the  dia- 


308 


THE    KKSl'IRATION 


phragm  descends  and  crowds  the  viscera  against  the  vena  cava,  with 
the  result  that  at  first  more  blood  is  squeezed  into  the  thorax  and  the 
blood  pressure  tends  slightly  to  rise.  After  this  initial  effect,  how- 
ever, the  compression  of  the  vena  cava  causes  less  blood  to  reach  the 
thorax,  and  the  arterial  blood  pressure  falls.  The  conditions  will  be 
exactly  reversed  on  expiration.  The  initial  effect  of  thoracic  inspira- 
tion is,  therefore,  to  make  the  arterial  blood  pressure  fall,  and  the  in- 
itial   effeet  of  abdominal    inspiration,   to   make   it  rise.      The   net   effect 


A.  ABDOMEN. 


HJUUU 


QUMJU 


Fig.  110. — Effect  of  abdominal  and  chest  breathing  on  the  pulse  and  blood  pressure  of  man. 
Abdominal  inspiration  raises  the  pressure  and  diminishes  the  amplitude  of  the  pulse  curve.  Thoracic 
inspiration   less    clearly    lowers   the   pressure.      Expiration    has    the    opposite    effects.      (From    Lewis.) 


produced  will  be  the  algebraic  sum  of  these  two  opposing  influences 
(see  Fig.  110). 

Another  factor  that  comes  into  play  in  determining  the  effect  of  the 
respiratory  movements  on  the  cardiac  output  acts  through  the  changes 
in  the  pericardial  pressure.  When  this  is  lowered,  as  early  in  inspira- 
tion, it  encourages  diastole,  thus  causing  better  filling  and  therefore 
better  discharge  from  the  heart. 

These  considerations  taken  together  make  it  easy  to  understand  the 
changes  in  blood  pressure,  particularly  in  the  veins,  which  occur  when 
a  forced  inspiratory  or  expiratory  movement  is  made  with  the  glottis 
closed.     A  forced  expiration  of  this  nature   occurs  during  the  acts  of 


RESPIRATION  309 

defecation  and  parturition;  as  yirell  as  in  the  first  stages  of  coughing;  it, 
is  also  produced  by  blowing  into  a  tube,  or  against  some  resistance. 
On  account  of  the  positive  pressure  that  is  brought  to  bear  on  the  veins 
as  they  enter  the  thorax,  the  venous  pressure  suddenly  rises,  slowing 
down  the  flow  of  blood  through  the  capillaries  and  causing  bulging  of 
the  veins  and,  if  the  effect  is  sustained,  cyanosis.  On  the  arterial 
side  of  the  vascular  system,  after  a  momentary  rise  caused  by  the 
squeezing  out  into  the  left  side  of  the  heart  of  the  blood  in  the  capil- 
laries of  the  lungs,  there  is  a  more  permanent  fall  in  pressure  due  to 
the  fact  that  less  blood  is  now  getting  from  the  right  side  to  the  left 
side  of  the  heart.  After  some  time  the  pressure  begins  to  rise  again, 
partly  on  account  of  the  back  pressure  through  the  capillary  vessels 
and  partly  because  of  vasoconstriction  as  a  result  of  asphyxial 
conditions. 

In  the  opposite  condition,  during  a  forced  inspiratory  movement  with 
the  glottis  closed  or  with  the  mouth  attached  to  some  tube  through 
which  the  attempt  is  made  to  suck  air,  the  thoracic  cavities  open  up 
without  the  lungs  being  able  to  occupy  completely  the  extra  space. 
The  dilatation  of  the  veins  and  other  thin-walled  structures  in  the  tho- 
rax thus  causes  an  immediate  fall  in  both  the  venous  and  the  arterial 
pressure — in  the  venous,  because  the  blood  is  sucked  toward  the  large 
vessels  in  the  thorax  and  lungs,  and  in  the  arterial,  because  the  blood  is 
now  delayed  in  its  passage  from  the  right  to  the  left  side  of  the  heart. 
If  this  condition  is  maintained,  the  arterial  pressure  may  recover  some- 
what, but  that  in  the  veins  is  permanently  lowered. 


CHAPTER  XXXV 

THE  MECHANICS  OF  RESPIRATION  (Cont'd) 

VARIATIONS  IN  THE  DEAD  SPACE,  THE  RESIDUAL  AIR  AND 
MID-CAPACITY,    AND    THE    VITAL    CAPACITY    IN    VARI-    . 
OUS    PHYSIOLOGIC    AND    PATHOLOGIC    CONDITIONS 

By  R.  G.  Pearce,  B.Ai,  M.D. 

Dead  Space 

Under  ordinary  conditions  of  breathing  the  dead  space  is  fairly  con- 
stant in  volume.  Haldane5  and  Henderson6  believe  that  it  may  be  in- 
creased by  400  per  cent  in  maximal  deep  breathing,  and  that  the  in- 
crease is  due  to  the  passive  stretching  of  the  lower  air  sacs.  Although 
such  large  variations  in  the  capacity  of  the  dead  space  has  not  been  ob- 
served by  Krogh  and  Lindhard7  or  by  R.  G.  Pearce,8  it  is  undoubted 
that  moderate  rhythmic  variations  may  occur.  Even  in  deeper  breath- 
ing (1500  c.c.  or  over),  a  slight  increase,  which  with  maximum  breaths 
may  amount  to  100  c.c,  can  be  demonstrated.  This  is  not  surprising 
when  we  remember  that  the  walls  of  the  bronchi  and  bronchioles  are 
made  up  largely  of  readily  expansible  tissue  (elastic  and  smooth-muscle 
fibers).  As  the  respirations  become  deeper  and  the  expanding  force  of 
the  inspiratory  movements  of  the  thorax  becomes  more  pronounced,  the 
diameter  of  the  bronchi  and  bronchioles  will  enlarge  proportionately — 
that  is,  the  diameter  or  circumference  will  increase  in  direct  proportion 
to  this  force;  but  the  area  of  the  cross  section  of  the  bronchi  (i.  e.,  the 
capacity)  will  increase  as  the  square  of  the  diameter.  This  depends  on 
the  fact  that  the  area  of  a  circle  is  increased  by  125  per  cent  when  the 
diameter  is  increased  by  50  per  cent,  and  by  about  300  per  cent  when 
the  diameter  is  increased  by  100  per  cent. 

The  capacity  of  the  dead  space  has  a  certain  clinical  significance. 
Siebeek9  has  estimated  that  the  dead  space  may  increase  by  100  c.c.  in 
asthma,  but  others  believe  that  the  increase  may  be  greater.  One  rea- 
son for  the  discordant  results  lies  in  the  fact  that  the  percentage  of 
C02  found  in  the  alveolar  air  obtained  by  the  Haldane-Priestley  method 
has  been  used  as  one  of  the  basic  figures  in  the  determination  of  the 

310 


THE    MECHANICS  OF   RESPIRATION  311 

capacity  of  the  air  passages.  As,  explained  elsewhere  (page  344),  the  pro- 
longation of  expi  ration  required  to  obtain  the  sample  of  alveolar  air  by  Hi  is 
method  gives  figures  that  arc  too  high  even  under  normal  conditions, 
and  it  is  plain  that  this  error  will  be  exaggerated  in  asthma,  where  the 
expiration  is  greatly  prolonged.  An  increase  in  the  capacity  of  the 
dead  space  must  be  accompanied  by  an  increase  in  the  respiratory  vol- 
ume if  the  alveoli  are  to  be  adequately  ventilated.  It  has  been  thought 
by  some  clinicians  that  the  difficulty  in  asthma,  emphysema  and  car- 
diac decompensation  may  lie  in  part  in  an  increase  in  the  dead  space. 
Careful  estimations  of  the  dead  space  in  these  conditions,  however, 
fail  to  demonstrate  any  great  variation. 

An  explanation  of  the  fact  that  the  dead  space  in  emphysematous 
patients  has  been  found  to  be  generally  large  when  determined  by  the 
Ilaldane-Priestley  method  (see  page  340),  and  also  for  some  of  the  cliiv 
ical  phenomena  accompanying  the  condition,  may  be  as  follows:  In 
emphysema  the  walls  of  the  alveoli,  especially  about  the  lateral  and 
lower  borders  of  the  lungs,  have  lost  their  elasticity  and  fail  to  expand 
or  relax  properly  during  the  respiratory  cycle.  As  a  result  the  air  in 
these  alveoli  remains  relatively  unchanged  except  when  forced  respira- 
tions are  made.  "When  a  sample  of  alveolar  air  is  taken  directly,  this 
dead  air  is  pushed  out  of  the  distended  and  diseased  alveoli  by  the 
forced  respiration  required  in  the  direct  sampling  of  the  alveolar  air. 
Since  the  air  in  these  alveoli  has  been  in  contact  with  the  blood  enter- 
ing the  lungs,  it  has  a  high  C02  content,  which  results,  when  compared 
with  the  uniformly  low  C02  content  found  in  the  tidal  air,  in  giving  a 
large  figure  for  the  dead  space.  Since  the  capacity  of  the  dead  space 
is  not  increased,  the  blood  in  the  normal  alveoli  is  probably  being  super- 
ventilated  in  order  to  compensate  for  the  high  C02  tension  in  the  blood 
entering  the  left  heart  from  the  diseased  alveoli.  However,  the  02 
content  of  the  blood  leaving  the  sound  alveoli  is  practically  normal  (be- 
cause supcrventilation  can  not  cause  it  to  take  up  more),  and  can  not 
compensate  for  the  low  02  content  in  the  blood  coming  from  the  dis- 
eased alveoli,  the  net  effect  being  therefore  a  low  tension  of  02  in  the 
blood  leaving  the  heart,  which  accounts  for  the  cyanosis  often  seen  in 
emphysema  (Pearce).  A  somewhat  similar  explanation  can  be  given 
for  the  cyanosis  present  in  pulmonary  edema,  if  we  assume  that  all  the 
alveoli  in  this  condition  do  not  share  alike  in  the  edema  (Hoover). 

The  Residual  Air  and  Mid-capacity  of  the  Lungs 

During  muscular  exercise  the  residual  air  of  the  lungs  is  increased, 
and  the  vital  capacity  decreased  (Bohr).     This  causes  the  lungs  to  as- 


312  THE   RESPIRATION 

sume  a  more  inflated  condition  between  breaths  or,  as  it  has  been  clum- 
sily styled,  a  greater  mid-capacity.  These  changes  may  serve  as  a 
physiologic  method  for  increasing  the  efficiency  of  alveolar  ventilation 
so  as  to  meet  the  greater  needs  of  the  body.  This  is  partly  because  the 
pulmonary  vessels  become  dilated  and  the  bloodflow  through  the  lungs 
is  favored,  and  partly  because  of  the  influence  of  the  reserve  and  sup- 
plemental airs  on  the  tension  of  the  arterial  blood  gases  during  the  res- 
piratory cycle.  For  example,  if  the  lungs  were  completely  depleted 
of  air  during  expiration,  the  blood  leaving'  them  at  the  end  of  this  act 
would  be  entirely  venous.  On  the  other  hand,  if  the  amount  of  air  left 
in  the  lungs  at  the  end  of  expiration  Avere  above  the  normal  amount, 
each  increment  of  CO,  given  off  from  the  blood,  or  of  02  absorbed  by 
it  would  produce  less  change  in  the  pressure  of  the  C02  or  02. 

The  importance  of  these  influences  will  be  seen  from  the  following 
figures.  If  the  residual  and  supplemental  air  amounts  to  2000  c.c,  and 
the  percentage  of  C02  in  the  alveolar  air  at  the  end  of  expiration  is 
5  per  cent,  then  100  c.c.  of  C02  must  be  present  in  the  lungs.  In  a  con- 
dition of  bodily  rest  about  20  c.c.  of  this  gas  is  excreted  during  a  res- 
piratory cycle,  so  that  if  the  breath  Avere  held  during  this  period,  the 
percentage  of  C02  Avould  rise  from  5  to  6  per  cent,  and  an  inspiration  of 
400  c.c.  would  be  required  to  bring  the  air  in  the  lungs  back  to  5  per 
cent  of  C02.  On  the  other  hand,  if  the  residual  and  supplemental  air 
amounted  to  3000  c.c.  with  5  per  cent  of  C02  in  the  alveolar  air  at  the 
end  of  the  expiration,  there  would  be  150  c.c.  of  C02  in  the  lungs  at 
the  end  of  the  expiration,  so  that  holding  the  breath  for  the  time  of  the 
respiratory  cycle  Avould  raise  the  percentage  of  C02  only  to  5.66  (pro- 
vided the  production  of  C02  Avas  the  same  as  in  the  first  case),  and  an 
inspiration  of  600  c.c.  would-  be  necessary  to  reduce  it  to  the  normal 
expiratory  figure.  Or,  putting  it  another  way,  the  production  of  CO, 
can  be  increased  50  per  cent  in  the  time  of  a  respiratory  cycle  Avithout 
affecting  the  tension  of  gases  in  the  lungs,  provided  the  residual  and 
supplemental  air  and  the  volume  of  the  respiration  are  increased  50 
per  cent.  If  only  one  of  the  factors  is  changed,  hoAvever,  then  the  bal- 
ance of  the  respiration  must  be  disturbed,  and  the  greater  Arariation 
in  the  tension  of  the  gases  in  the  arterial  blood  must  occur  at  the  dif- 
ferent phases  of  the  respiratory  cycle.  Bohr  and  Siebeck  haA-e  shoAvn 
that  the  residual  air  is  invariably  increased  in  emphysema  and  that  the 
mid-capacity  of  the  lungs  is  likeAvise  increased;  and  it  Avould  appear 
from  Siebeck's  data  that  a  similar  condition  must  be  present  in  cases  of 
decompensated  heart. 

Patients   suffering   from    dyspnea,    particularly    those    suffering   from 


Till:    MF.CIIANICK    OF    RKSIMKATION 


313 


cardiac  dyspnea,  can  not  breathe  as  comfortably  when  lying  as  when 
sitting.  This  condition  is  known  as  orthopnea.  The  advantage  of  the  sit- 
ting over  t lie  lying  position  for  breathing  can  not  be  satisfactorily  ex- 
plained. The  greater  vital  capacity  in  the  upright  position;  the  favor- 
ing of  the  return  of  the  venous  blood  from  the  cerebral  vessels  by 
g cavity;  the  increased  caliber  of  the  pulmonary  vessels  because  of  the 
enlarged  thoracic  cavity  (sec  page  318)  ;  and  the  increase  in  the  reserve 
air  of  the  lungs — are  all  factors  to  be  considered. 

The  Vital  Capacity. — At  one  time  it  was  thought  that  the  vital  capacity 
of  the  lungs  was  related  to  their  ventilatory  capabilities,  but  for  years 
the  determination  of  this  value  in  patients  has  been  considered  unimpor- 
tant. Recently  Peabody  and  Wentworth10  have  called  attention  to  the 
fact  that  patients  with  heart  disease  become  dyspneic  more  readily  than 
do  healthy  subjects,  and  that  this  tendency  seems  to  depend  largely 
on  their  inability  to  increase  the  depth  of  the  respiration  in  a  normal 
manner.  They  find  that  this  inability  to.  breathe  deeply  corresponds  to 
a  diminished  vital  capacity  of  the  lungs  as  measured  in  a  spirometer, 
by  the  volume  of  the  greatest  possible  expiration  after  the  deepest  in- 
spiration. They  believe  that  any  condition  which  limits  the  possibility 
of  increasing  the  minute  volume  of  air  breathed  must  be  an  important 
factor  in  the  production  of  dyspnea. 

In  normal  adults  the  following  averages  (Table  I),  were  secured  from 
a  large  series  of  clinical  cases.  The  subjects  are  grouped  into  two 
classes,  each  group  being  subdivided  according  to  height. 

Table  I 

The  Vital   Capacity   of  the  Lungs   of   Normal   Males 


GROUP 

NUMBER 
STUDIED 

HEIGHT  IN 

FEET  AND 

INCHES 

NORMAL 

VITAL 

CAPACITY 

C.C. 

NUMBER 
WITHIN 
10%     OF 
NORMAL 

HIGHEST 

VITAL 
CAPACITY 

LOWEST 

VITAL 
CAPACITY 

HIGH- 
EST 

% 

LOWEST 
% 

NUMBER 

BELOW 

907c  of 

NORMAL 

I 
II 

III 

14 
44 

38 

6'  + 

Over   5' 

8l/2"  to  6' 

5'   3"  to 

5'  8V2" 

5,100 
4,800 

4,000 

9 

41 

31 

7,180 
5,800 

5,080 

5,030 
4,300 

3,450 

141 
121 

127 

99 

90 

86 

0 
0 

1 

The   Vital   Capacity  of  the 

Lungs  of  Normal  Females 

I 

10 

Over    5' 

6" 
Over   5' 

3,275 

5 

4,075 

2,800 

124 

86 

2 

II 

13 

3,050 

Q 

3,425 

2,660 

112 

88 

2 

4"    to    5' 
f>" 

III 

21 

5'   4"   or 

less 

2,825 

16 

3,820 

2,500 

135 

89 

1 

(Peabody   and   Wentworth.) 


It  would  appear  that  in  normal  people  the  vital  capacity  is  at  least 
85  per  cent,  and  almost  always  90  per  cent  or  more,  of  the  standard 
adopted  for  each  group.  In  elderly  persons  a  slight  decrease  from  these 
standards  may  be  expected. 


314  THE   RESPIRATION 


Table  II 


The  Relation  op  the  Vital  Capacity  of  the  Lungs  to  the  Clinical  Condition  in 
Patients  with  Heart  Disease* 


group 

VITAL 

NUM- 

MOR- 

SYMPTOMS 

WORK- 

REMARKS 

CAPACITY 

BER  OP 

TALITY 

OF  DECOM- 

ING 

% 

CASES 

% 

PENSATION 

% 

% 

I 

90  - 

25 

0 

0 

92 

Few  symptoms  ref- 
erable to  heart. 

II 

70  to  90 

41 

5 

2 

54 

History  of  dyspnea 
with  exertion,  yet 
able  to  do  moder- 
ate work. 

III 

40  to  70 

07 

17 

89 

7 

Dyspnea  with  mod- 
e  r  a  t  e  exercise. 
Few  able  to  work. 

IV 

Under  40 

23 

61 

100 

0 

Bedridden,  with 
marked  signs  of 
cardiac  insuf- 
ficiency. 

(Peabody  and  Wentworth.) 

'Certain  cases  were  tested  several  times  and,  owing  to  changes  in  the  vital  capacity  they  appear 
in  more  than  one  group.  In  the  "mortality"  column  they  are  included  only  in  the  lowest  group  into 
which  they  fell.  "Symptoms  of  decompensation"  indicate  dyspnea  while  at  rest  in  bed  or  on  very 
slight  exertion.  _  Under  "working"  are  included  only  those  actually  at  work,  and  able  to  continue. 
Many  other  patients  in  Group  II  were  able  to  work,  but  they  are  not  included  as  they  were  still  in 
the  hospital. 

Table  II  shows  that  there  is  a  remarkably  close  relationship  betwreen 
the  clinical  condition  of  cardiac  patients,  particularly  as  regards  the 
tendency  to  dyspnea,  and  the  vital  capacity  of  the  lungs.  Peabody  and 
Wentworth  believe  that  the  determination  of  the  vital  capacity  affords 
a  clinical  test  as  to  the  functional  condition  of  the  heart,  since  compen- 
sated patients  who  do  not  complain  of  dyspnea  on  exertion  have  a  nor- 
mal vital  capacity.  Patients  with  more  serious  disease  in  whom  dyspnea 
is  a  prominent  symptom,  have  a  low  vital  capacity;  and  the  decrease  in 
vital  capacity  runs  parallel  with  the  clinical  condition.  As  a  patient 
improves,  his  vital  capacity  tends  to  rise ;  as  he  becomes  Avorse,  it  tends 
to  fall.  In  other  diseases  in  Avhich  mechanical  conditions  interfere  with 
the  movements  of  the  lungs,  the  tendency  to  dyspnea  corresponds  closely 
to  the  decrease  in  the  vital  capacity.  The  cause  of  the  decrease  in  the 
vital  capacity  of  the  lung  in  cardiac  decompensation  is  difficult  to  ex- 
plain satisfactorily.  It  may  be  the  limitation  in  the  movements  of  the 
lungs  produced  by  engorgement  of  the  pulmonary  vessels,  by  the  weak- 
ness of  the  intercostal  muscles,  the  rigidity  of  the  bony  thorax, 
emphysema,  or  accumulation  of  fluid  in  the  pleural  cavities. 

In  cardiac  disease  the  air  in  the  lungs  at  the  end  of  a  normal  expiration 
is  usually  increased.  This  is  similar  to  the  condition  which  attends  exer- 
cise, and  is  probably  a  physiologic  adaptation  to  give  optimum  aeration 
to  the  blood,  as  explained  above. 


CHAPTER  XXXVI 

THE  MECHANICS  OF  RESPIRATION    (Cont'd) 

THE  MECHANISM  BY  WHICH  THE  CHANGES  IN  CAPACITY  OF 
THE  THORAX  AND  LUNGS  ARE  BROUGHT  ABOUT 

By  R.  G.  Pearce,  B.A.,  M.D. 

The  changes  thai  lake  place  in  the  form  and  the  dimensions  of  the 
thorax  during  respiration  are  brought  about  by  movements  of  the  ribs, 
diaphragm,  sternum,  and  vertebra}.  The  share  which  each  plays  must 
be  considered  separately. 

The  Movements  of  the  Ribs 

The  first  seven  pairs  of  ribs  progressively  increase  in  length,  and  are 
attached  directly  to  the  sternum  by  cartilaginous  bands.  The  eighth  to 
the  twelfth  pairs  progressively  decrease  in  length,  and  as  far  as  the 
tenth  they  are  indirectly  attached  to  the  sternum  by  cartilages  which  join 
the  seventh.  The  eleventh  and  twelfth  have  their  anterior  ends  free,  and 
may  be  considered  a  part  of  the  abdominal  wall  and  not  an  intrinsic  part 
of  the  thoracic  cage. 

Each  pair  of  ribs,  together  with  its  articulating  cartilage  and  vertebrae, 
forms  a  ring,  the  plane  of  which  is  directed  forward  and  downward. 
The  spinal  articulations  of  the  upper  ribs  differ  from  those  of  the  lower 
ones.  In  the  former  the  articulations  on  the  tubercle  exist  as  convex 
ovoid  facets,  which  fit  into  corresponding  hollow  facets  on  the  transverse 
processes  of  the  vertebrae,  while  the  corresponding  facets  of  the  lower 
ribs  are  flat.  Each  transverse  process  from  above  downward  is  tilted  a 
little  more  backward  than  the  one  above,  so  that  the  angle  at  which  the 
ribs  are  set  to  the  spine  increases  from  above  downward.  This  manner 
of  articulation  of  the  upper  ribs  with  the  vertebrae  prevents  any  rotation 
in  the  spinosternal  axis,  so  that  there  can  be  no  so-called  bucket-handle 
movement  in  this  region  (Keith).  The  articulation,  hoAvever,  allows  the 
neck  of  the  rib  to  rotate  in  an  axis  approximately  transverse  to  the  body. 
The  angle  which  the  shaft  of  the  rib  makes  near  its  neck,  together  with 
the  arch  of  the  shaft,  which  is  directed  downward  and  forward,  has  the 
effect  of  causing  the  transverse  rotation  of  the  neck  of  the  rib  to  be 

315 


316 


THE   RESPIRATION 


converted  into  an  upward  movement,  -which  is  greatest  in  that  part  of  the 
shaft  lying  parallel  to  the  axis  of  rotation  of  the  neck  (Fig.  111). 

The  upper  ribs  from  the  first  to  the  fifth  form  a  cone-shaped  top  to  the 
thorax,  whereas  the  lower  ones  form  a  vertical  series,  each  being  situated 
almost  directly  above  its  neighbor.  The  upper  set  is  arranged  for  the 
expansion  of  the  conical  upper  lobe  of  the  lungs,  the  lower  for  the  ex- 
pansion of  the  more  or  less  cylindrical  lower  lobes.  During  inspiration 
the  anteroposterior  diameter  of  the  conical  portion  of  the  thorax  in- 
creases, because  the  ribs,  together  with  the  sternal  connections,  move 
through  progressively  increasing  arches,  and  each  lower  rib  tends  to  over- 
ride the  rib  just  above.     The  maximal  rise  of  the  ribs  from  the  first  to  the 


Fig.    111. — A,   first   dorsal   vertebra;   B,   sixth   dorsal   vertebra   and    rib.      Axis    of    rotation    shown    in 

each    case. 


tenth  during  inspiration  shifts  more  and  more  from  the  anterior  to  the 
lateral  aspects  of  the  thorax,  because  the  angle  formed  by  the  shaft  near 
the  neck  of  the  rib  approaches  nearer  to  the  articulating  joints  on  the 
vertebra?. 

An  examination  of  the  shape  of  the  first  rib,  its  relationship  to  adjacent 
structures  and  its  movements,  shows  that  it  differs  from  the  others  in 
its  respiratory  function.  The  first  pair  of  ribs  and  the  manubrium  sterni 
are  bound  closely  together  by  short,  wide  costal  cartilages,  and  form  a 
structural  unit  which  Keith1  calls  the  thoracic  operculum.  This  lid  is 
articulated  behind  with  the  first  thoracic  vertebra  by  a  joint,  which  is 
more  nearly  transverse  than  that  of  the  rest  of  the  costal  series;  and  in 
front  with  the  manubrium,  which  is  also  articulated  with  the  clavicles 


THE    MECHANICS   OP    RESPIRATION  .".17 

above  and  with  the  body  of  the  sternum  below.  The  freedom  of  move- 
ment al  the  angle  which  the  manubrium  makes  with  the  sternum  a1  tins 
joint  is  related  to  the  type  of  breathing.  When  the  lower  portion  of  the 
sternum  is  elevated  during  inspiration,  the  movement  of  the  joint  is  not 
free,  but  when  the  sternum  is  retracted,  the  movement  at  the  angle  may 
amount  to  16°.  Lack  of  movement  of  the  sternal  manubrial  joint  has 
been  considered  by  some  physicians  as  one  of  the  predisposing  causes  of 
pulmonary  tuberculosis.  During  inspiration,  the  first  rib  and  its  anterior 
attachments  are  raised  by  the  scaleni,  and  serve  as  a  point  towards  which 
the  second,  third,  fourth  and  fifth  ribs  are  elevated.  During  expiration, 
they  are  depressed  toward  the  lower  ribs,  which  form  a  more  or  less 
fixed  base. 

The  combined  effect  of  these  influences  is  to  produce  a  motion  of  the 
upper  ribs  which  is  described  by  the  clinician  as  being  undulatory.  This 
movement  is  more  apparent  in  the  upper  part  of  the  thorax,  because 
here  the  relative  difference  in  the  length  of  the  ribs  is  greatest.  Hoover 
attributes  a  certain  diagnostic  significance  to  loss  of  the  undulatory 
movement,  diminution  in  the  extensibility  of  the  underlying  lungs  causing 
it  to  become  less  or  to  disappear.  The  phenomenon  is  elicited  by  placing 
the  tip  of  the  ring  finger  on  the  second  rib  in  the  midclavicular  line,  the 
tip  of  the  middle  finger  on  the  third  rib  midway  between  the  midclavicu- 
lar and  anteroaxillary  line,  and  the  tip  of  the  index  finger  on  the  fourth 
rib  in  the  midaxillary  line.  The  patient  is  then  instructed  to  make  a 
moderately  rapid  and  deep  inspiration.  The  finger  on  the  third  rib  will 
be  observed  to  move  farther  than  that  on  the  second  rib,  and  the  finger 
on  the  fourth,  rib  will  move  farther  than  that  on  the  third.  The  move- 
ment of  each  rib  from  above  downward  succeeds  and  exceeds  that  in 
the  rib  just  above. 

When  there  is  a  moderate  degree  of  impairment  in  the  ventilation  of 
the  upper  lobe,  the  three  ribs  move  in  unison  and  through  the  same  dis- 
tance, so  that  the  undulatory  movement  is  lost  although  the  ribs  involved 
may  exhibit  a  considerable  excursion.  The  undulatory  movement  is  also 
impaired  by  any  disease  which  encroaches  on  the  air  spaces,  invades  the 
interstitial  tissue  of  the  lung,  or  displaces  the  lung  as  in  the  case  of  an 
enlarged  heart  or  a  distended  pericardial  sac.  Another  possible  factor 
in  this  phenomenon  is  that  any  inflammatory  process  in  the  lung  or  ad- 
jacent tissue  will  produce  a  reflex  inhibition  of  the  muscles  of  the  ribs, 
and  thus  limit  the  expansion  of  the  thorax. 

The  axis  of  movement  of  the  lower  ribs,  as  of  the  upper  ribs,  accurately 
corresponds  with  that  indicated  by  their  articulation  with  the  vertebrae, 
because  the  muscles  attached  to  them,  as  well  as  the  diaphragm,  influence 
their  movements  to  a  large  extent.     Anteriorly  the  lower  ribs  from  the 


318 


THE   RESPIRATION 


sixth  to  the  tenth  are  joined  to  the  sternum  by  the  cartilages  which  unite 
the  sixth,  seventh,  eighth,  ninth,  and  tenth,  so  that  any  movement  in 
which  the  ribs  are  raised  is  accompanied  by  an  anterior  movement  of  the 
sternum  (Fig.  112).  The  ribs  are  so  articulated  to  the  spinal  column  that 
the  inspiratory  act  causes  the  lateral  and  anterior  part  of  each  rib  arch 
to  move  forward  and  outward  more  than  the  one  above  it. 

In  natural  breathing  in  the  standing  or  sitting  posture  there  is  a 
slight  extension  of  the  spine  during  inspiration.  This  serves  to  increase 
all  diameters  of  the  thorax  and  its  absence  is  undoubtedly  an  important 


Fig.  112. — Lower  half  of  the  thorax  from  the  6th  dorsal  to  the  4th  vertebra,  seen  from  the 
front.  c,  cnsiform  process;  d,  d' ,  aorta;  e,  esophagus;  f,  aperture  in  tendon  of  diaphragm  for 
passage  of  vena  cava  inferior;  I,  2,  .?,  trilobate  expansions  of  tendinous  center  of  diaphragm;  4,  5, 
costal  portions,  right  and  left,  of  diaphragm  muscle;  6,  right  cms  of  diaphragm;  S,  9,  internal 
intercostal  muscles,  which  are  absent  near  the  vertebral  column,  where  it  joins  9  and  9,  the  ex- 
ternal   intercostals;    10,   10,   subcostal   muscles   of   left   side.      (From    Luschka.) 

contributory  factor  in  reducing  the  vital  capacity  of  an  individual  when 
lying  on  the  back.  Figures  given  by  Hutchinson  for  the  effect  which 
posture  has  on  the  vital  capacity  are  of  interest  because  of  their  bearing 
on  the  cause  of  orthopnea.  In  the  same  individual  he  found  the  following 
vital  capacities: 

Standing  4300  c.c. 

Sitting  4200  c.c. 

Supine  3800  c.c. 

Prone  3620  c.c. 


THE    MECHANICS   OP   RESPIRATION 


319 


The  Action  of  the  Musculature  of  the  Ribs 

In  a  general  way,  the  external  intercostal  muscles  may  be  considered 

as  a  broad  extension  of  the  scalene  muscles  over  the  thoracic  walls,  with 
the  ribs  as  intersections.     The  scalcni   serve  to  fix  the   position  of  the 


Fig.  113. — Intercostal  muscles  of  5th  and  6th  spaces.  A,  side  view;  B,  back  view;  IV,  4th 
dorsal  vertebra;  V,  5th  rib  and  cartilage;  J,  /,  M.  levatores  costarum,  2,  2,  external  intercostals; 
3,  3,  internal  intercostals,  exposed  by  removal  of  the  external  muscles.  In  A,  there  are  no  external 
intercostals  in  the  intercartilaginous  spaces;  in  B  there  are  no  intercostals  near  the  vertebral 
column.      (From  Allen  Thomson.) 

first  rib  so  that  it  forms  an  anchorage  for  the  action  of  the  external 
intercostal  muscles  in  raising  the  lower  ribs.  They  also  raise  the  upper 
three  pairs  of  ribs  along  with  the  manubrium  and  sternum. 

The  function  of  the  intercostal  muscles  has  been  the  subject  of  much 


Fig.  114. — Hamberger's  schema  to  demonstrate  the  functional  antagonism  of  internal  and  ex- 
ternal  intercostals. 

When  the  ribs  ac  and  bd  pass  into  the  inspiratory  positions  ag  and  bf,  the  intercostal  space 
dilates  {bh  is  greater  than  ab)  ;  the  sternum  gf  moves  away  from  the  vertebral  column  ab  {bf  is 
greater  than  be) ;  the  fibers  of  the  external  intercostals  ak  shorten  (ak  is  greater  than  al) ;  and 
those  of  the  internal  intercostals  ck  lengthen  (ck  is  greater  than  Ig).  The  reverse  occurs  when 
the    inspiratory    position    is    taken.       (From    Luciani's    Human    Physiology.) 


320 


THE    RESPIRATION 


debate,  and  can  not  be  said  to  be  definitely  settled.  The  direction  of  the 
fibers  in  the  internal  intercostals  indicates  that  they  are  expiratory  in 
function,  since  they  can  not  shorten  in  the  inspiratory  position ;  while, 
on  the  other  hand,  the  fibers  of  the  external  intercostals  can  not  shorten 
in  the  expiratory  position,  and  hence  must  be  considered  inspiratory  in 
character  (Fig.  113).  In  1751  Hamberger  showed  that  mechanically  this 
is  the  case,  and  gave  the  schema  shown  in  Fig.  114. 

The    function   of   the    intercartilaginous    muscles,    however,    must   be 
inspiratory,  as  is  shown  in  Fig.  115. 


Fig.  115. — Schema  to  demonstrate  that  the  function  of  the  internal  intercartilaginous  intercos- 
tals   is    identical    with    that    of    the    external    interosseous    intercostals. 

The  ribs  and  costal  cartilage  may  be  regarded  as  rods  bent  at  the  angles  acd  and  bef,  in 
which  the  articular  points  c  and  e  represent  the  symphysis  between  the  bony  and  the  cartilaginous 
parts  on  which  traction  is  made.  During  inspiration  the  fibers  of  the  intercartilaginous  muscles, 
which  have  the  direction  gh,  move  the  sternum  df  away  from  the  vertebral  column  ab,  like  the 
fibers  of  the  external  intercostals,  which  run  in  the  direction  kl.  During  this  double  action  the 
angles  c  and  c  must  be  decreased,  because  the  muscles  of  the  upper  intercostal  spaces  work  simul- 
taneously, and  the  entire  thorax  is  slightly  elevated  during  inspiration.  From  this  scheme  it  is 
apparent  that  the  external  intercostals  and  the  intercartilaginous  muscles  must  be  the  same.  (From 
Luciani's  Human  Physiology.) 


The  Action  of  the  Diaphragm 

It  is  possible,  however,  that  the  main  function  of  both  the  intercostal 
muscles  is  to  regulate  the  tone  of  the  intercostal  spaces  and  so  prevent 
their  suction  inwards  when  the  negative  pressure  in  the  thorax  increases 
(i.  e.,  suction  becomes  greater).  The  ascent  of  the  ribs,  while  producing  an 
increase  in  the  anteroposterior  and  transverse  diameters  of  the  thorax, 
would  decrease  the  vertical  diameter  if  this  was  not  counteracted  by  the 
fixation  of  the  lower  ribs  and  the  descent  of  the  diaphragm.  The  periph- 
eral edges  of  the  diaphragm  are  attached  behind  to  the  lumbar  vertebrae, 
laterally  to  the  lower  edges  of  the  six  lower  ribs  and  their  cartilages, 
and  in  front  to  the  tip  of  the  ensiform  cartilage.    The  fibers  converge  to 


THE    MECHANICS    OP    RESPIRATION  32] 

enter  the  central  tendon,  and  the  lateral  sheds  are  pressed  upward  by 
the  intraabdominal  positive  and  intrathoracic  negative  pressures,  so  thai 
they  form  a  dome-shaped  vault,  with  the  liver  in  the  right  side  and  the 
stomach  and  the  spleen  in  the  left. 

During  expiration  the  lateral  edges  of  the  diaphragm  are  in  eontad 
with  the  parietal  pleura  of  the  thoracic  cavity,  forming  whal  are  known 
as  the  pleural  sinuses.  During  inspiration  the  fibers  of  the  diaphragm 
shorten;  this  straightens  oul  the  arch  of  the  diaphragm  and  pulls  the 
lateral  edges  of  the  diaphragm  away  from  the  parietal  pleura,  thus  open- 
ing up  the  pleural  sinuses,  into  which  the  lungs  descend.  Usually  the 
opening  up  of  the  sinuses  is  accompanied  by  a  slight  retraction  of  the 
external  chest  wall,  which  is  known  as  Litten's  diaphragm  phenomenon. 
The  descent  of  the  diaphragm  may  produce  a  movement  of  from  10  to 
15  mm.  on  each  side,  which  accounts  for  a  rather  important  fraction  of 
the  volume  of  air  exchange  by  the  lungs.  The  central  portion  of  the 
diaphragm  does  not  move  much  in  normal  respiration,  but  in  forced 
respiration  its  movement  may  be  considerable. 

Because  of  its  attachments  to  the  lower  six  ribs,  the  contraction  of  the 
diaphragm  tends  to  pull  the  margins  of  the  ribs  towards  the  median  line, 
but  under  normal  conditions  this  movement  is  opposed  by  the  action  of 
the  external  intercostals  in  raising  the  ribs  and  expanding  the  horizontal 
diameters  of  the  thorax,  and  by  the  lower  vertebral  muscles,  which  fix 
the  position  of  the  lower  ribs. 

The  relative  part  which  the  diaphragm  and  the  external  intercostal 
muscles  plan  '"  the  widening  of  the  lower  part  of  the  thorax  is  of  some'i 
importance  from  the  standpoint  of  diagnosis.  It  has  generally  been  held 
that  the  contraction  of  the  diaphragm  produces  a  widening  of  the  lower 
part  of  the  thorax,  because  in  its  descent  it  presses  upon  the  abdominal 
viscera  and  so  distends  the  abdomen  and  pushes  out  the  lower  ribs. 
That  this  might  occur  seems  not  improbable,  but  Hoover2  has  recently 
shown  by  experimental  and  clinical  observations  that  the  flaring  in  the 
costal  margins  seen  in  normal  inspiration  depends  on  other  factors.  He 
calls  attention  to  the  fact  that  the  contraction  of  the  intercostals  raises 
the  ribs  and  increases  the  angular  divergence  of  the  subcostal  borders. 
This  widening  of  the  angle  made  by  the  costal  margins  at  the  tip  of  the 
sternum  is  very  pronounced  in  paralysis  of  the  diaphragm  while  in 
paralysis  of  the  intercostal  muscles,  the  costal  borders  are  drawn  towards 
the  median  line  and  the  subcostal  angle  is  decreased.  This  shows  that 
the  diaphragm  must  tend  to  diminish  the  angle. 

The  line  of  traction  of  the  diaphragm  is  a  straight  one  joining  the  cen- 
tral tendon  with  the  edge  of  the  ribs.  When  the  diaphragm  forms  a 
well-defined  arch,  it  exerts  its  traction   at  a   disadvantage,  and  the  ex- 


322 


THE   RESPIRATION 


Fig.   116. — Diagram    to    show    the    effect    of    high    and    low    positions    of    the    diaphragm    on    the 
costal   angle. 

Line   1.  Normal    position    of    diaphragm        Costal    margins    move    out    during    inspiration. 

Line  2.  High   position   of  diaphragm.      Normal,  outward   movement   of   costal   margins   accentuated. 

Line  3.  Low   position   of   diaphragm.      Costal   margins   move   in   during   inspiration. 

Line  4.  Very    low    position    of    diaphragm.      Costal    margins    move    out    during    inspiration. 

Line  S.  Actual   line  of  traction   of  diaphragm.      (From   T.    Wingate   Todd.) 


THE    Ml  <  ll  wms   OF    i;i  SPIR  \Tlo\ 


323 


Fig.    117.— Diagram   to   show    the   effect   of   clinical   displacements   of   the   diaphragm    on   the    costal 
angle. 

Line   1.  Normal   position  of  diaphragm.     Costal  margains  move  out  during  inspiration. 

2.  Position  of  diaphragm  in  general  cardiac  enlargement.     Costal  margin  from  ensiform  to  ninth 
rib   moves   toward   median   line. 

3.  Position    of    diaphragm    in    left-sided    cardiac    enlargement.       Left    costal    margin    is    fixed    or 
moves   in   during    inspiration. 

4.  Position    of    diaphragm    in    right-sided    cardiac    enlargement.      Right    costal    margin    is    fixed    or 
moves   in   during  inspiration. 

5.  Costal   margin.      (From    T.    Wingate   Todd.) 


:!l'4  the  respiration 

tenia]  intercostals  have  the  mastery  and  cause  the  eostal  borders  to 
spread.  When  the  arch  of  the  diaphragm  is  depressed,  as  in  pleurisy 
with  effusion,  emphysema,  and  empyema,  the  line  of  traction  and  the 
line  of  the  muscular  fibers  of  the  diaphragm  correspond  more  closely, 
so  that  the  diaphragm  is  able  to  use  its  full  force  against  the  intercostal 
muscles,  with  the  result  that  the  costal  border  moves  towards  the  median 
line.  The  curves  of  the  different  fibers  of  the  diaphragm  vary  greatly; 
the  arch  is  much  less  marked  in  the  portion  attached  to  the  costal  margin 
near  the  median  line  than  in  that  attached  in  the  axillary  line.  For  this 
reason  the  anterolateral  part  of  the  diaphragm  requires  less  depression 
to  give  it  a  horizontal  position  than  is  required  for  parts  occupying  a 
more  lateral  position.  A  small  pericardial  effusion  or  an  increase  in  the 
size  of  the  heart  may  therefore  depress  the  diaphragm  sufficiently  to  give 
it  mastery  over  the  intercostals  in  the  front  portion,  so  that  the  costal 
border  may  here  move  towards  the  midline,  while  the  lower  borders 
move  in  a  perfectly  normal  manner  (see  Figs.  116  and  117). 

During  forced  breathing  several  muscles  are  brought  into  play,  among 
the  most  important  of  which  are  the  scaleni,  sternomastoid,  trapezius, 
pectorals,  rhomboids,  and  serratus  magnus. 

There  has  been  considerable  debate  as  to  whether  expiration  is  normally 
an  active  or  a  passive  process.  Undoubtedly  the  expiratory  phase  under 
normal  conditions  does  not  require  the  same  muscular  effort  as  does  that 
of  inspiration,  but  there  are  many  observations  which  indicate  that  ex- 
piration is  partly  under  muscular  control.  The  abdominal  musculature, 
for  example,  increases  iii  tone  during  expiration,  so  as  to  bring  about  a 
rise  in  the  abdominal  pressure,  with  the  result  that  the  relaxed  diaphragm 
is  pushed  up  into  the  thoracic  cavity.  To  this  extent  at  least,  expiration 
is  accompanied  by  increased  muscular  activity. 

Before  leaving  the  subject  of  the  diaphragmatic  movements,  reference 
must  be  made  to  the  recent  observations  of  Lee,  Guenther  and  Meleney" 
bearing  on  the  general  physiologic  properties  of  the  diaphragmatic 
muscle.  They  point  out  that  most  skeletal  muscles  in  the  living  body 
contract  with  varying  degrees  of  intensity  and  at  irregular  intervals, 
between  which  relatively  long  periods  of  rest  occur,  but  the  diaphragm 
from  birth  to  death  performs  a  continuous  succession  of  brief  contrac- 
tions of  fairly  regular  rhythm  and  uniform  extent,  alternating  with  brief 
periods  of  rest.  Its  muscle  fibers,  together  with  those  of  the  other 
respiratory  muscles,  therefore  hold  a  unique  position  among  skeletal 
muscles,  which  suggests  a  crude  analogy  with  that  of  the  heart.  They 
have  compared  the  physiologic  properties  of  the  diaphragm  with  those 
of  the  extensor  longus  digitorum,  the  sartorius,  and  the  soleus,  and  found 


THE    MECHANICS   <>F    RESPIRATION  325 

thai  the  diaphragm  is  composed  of  ;i  much  more  efficienl  muscular  tissue 

than  that  of  the  other  muscles. 

The  Effects  of  the  Respiratory  Movements  on  the  Lungs.  The  changes 
produced  in  the  dimensions  of  the  Lungs  by  the  inspiratory  expansion  of 

the  thoracic  cavity  are  not  uniform,  since  different  parts  of  these  struc- 
tures arc  not  equally  extensible.  Prom  an  anatomic  standpoint,  the 
lungs  may  be  divided  into  three  zones:  (  1 )  The  inner  or  rool  /one  contain- 
ing the  bronchus,  artery  and   vein,  and  their  main   subdivisions.     The 

large  amount  of  fibrous  tissue  in  tins  region  offers  great  resistance  to 
any  expanding  force.  (2)  The  intermediate  zone,  containing  the  vascular 
and  bronchial  ramifications  radiating  towards  the  surface  of  the  lungs, 
with  pulmonary  tissue  implanted  between  the  rays.  This  part  of  the 
lungs  lias  varying  degrees  of  extensibility,  the  pulmonary  tissue  having 
the  most  and  the  vascular  and  bronchial  the  least.  (3)  The  outer  zone. 
perhaps  25  to  30  mm.  in  depth,  composed  of  pulmonary  tissue  and 
equally  extensible  throughout  (Keith1).  The  expansion  of  the  lung  is 
accomplished  by  a  moving  apart  of  the  less  extensible  rays  of  tissue  so 
as  to  permit  the  expansion  of  the  more  extensible  pulmonary  tissue  be- 
tween them.  Keith  compares  the  mechanism  to  that  seen  in  the  opening 
of  a  Japanese  fan. 

Because  the  lung  expands  in  the  direction  of  least  resistance,  study 
of  the  inflated  dead  lung  does  not  reveal  the  normal  expansion  brought 
about  by  the  thoracic  movements.  In  the  living  body  expansion  is  more 
limited  in  some  regions  than  in  others.  Of  the  five  areas  which  may  be 
distinguished  on  the  surface  of  the  lungs,  three  are  in  contact  with  rela- 
tively immovable  parts  of  the  chest  wall,  and  therefore  can  not  be  ex- 
panded directly.  These  are:  the  mediastinal,  in  contact  with  the  pericar- 
dium and  the  structures  of  the  mediastinum;  the  dorsal  surface,  in  contact 
with  the  spinal  column  and  the  posterior  aspect  of  the  thoracic  cage,  and 
the  apical  surface.  The  motions  of  the  first  pair  of  ribs  and  the  manu- 
brium expand  chiefly  the  anterior  and  ventrolateral  part  of  the  apex 
of  the  lung,  and  have  only  an  indirect  influence  on  the  dorsal  part  of  the 
apex — i.  e.,  the  part  lying  directly  in  front  of  the  necks  of  the  first  and 
second  ribs,  the  most  common  site  of  pulmonary  tuberculosis.  The  two 
surfaces  of  the  lungs  which  are  directly  expanded  are  the  diaphragmatic 
and  the  ventrolateral  or  sternocostal.  Meltzer4  found  that  the  negative 
pressure  in  the  thorax  during  inspiration  Mas  least  along  the  relatively 
stationary  walls  of  the  thorax,  and  greatest  in  the  regions  nearest  the 
diaphragm.  From  this  he  concludes  that  some  of  the  expanding  force 
is  lost  as  it  passes  through  the  lungs  to  the  surfaces  of  indirect  expansion. 
Many  observers  have  claimed  that  the  expansion  of  the  lung  does  not 
take  place  throughout  instantaneously  and  equally.     This  is  illustrated 


326  THE   RESPIRATION 

by  the  fact  that,  in  the  region  immediately  surrounding  a  localized  con- 
solidation, a  fluid  has  increased  resonance,  which  would  not  be  the  case 
if  the  relaxation  produced  was  equally  distributed  throughout  the  lung. 
The  root  of  the  lung,  which  has  generally  been  regarded  as  more  or 
less  fixed,  undergoes  in  normal  breathing  a  definite  forward,  downward 
and  outward  movement,  and  the  heart  shares  in  this  movement  (Keith). 
The  movements  of  the  lower  ribs  and  diaphragm  are  responsible  for  the 
expansion  of  the  lower  lobes  and  dorsal  portion  of  the  upper  lobes  of  the 
lungs,  whereas  the  movement  of  the  upper  five  ribs  expands  the  anterior 
portion  of  the  upper  lobes.  The  relative  infrequency  of  pleuritic  fric- 
tion-sounds and  pain  over  the  upper  lobes  as  compared  with  their  fre- 
quency over  the  lower  lobes  is  explained  by  the  fact  that  the  expansion 
of  the  upper  lobes  is  accomplished  with  little  displacement  of  the  pleural 
surfaces,  whereas  in  the  lower  lobes  expansion  is  accompanied  by  a  glid- 
ing of  the  lungs  across  the  ribs. 


CHAPTER  XXXVII 

THE  CONTROL  OF  THE  RESPIRATION 

The  participation  of  such  widespread  groups  of  muscles  in  the  respira- 
tory act  demands  that  some  mechanism  be  provided  to  insure  its  adequate 
control.  With  every  inspiration,  for  example,  the  muscles  of  the  alee 
nasi  act  so  as  to  cause  dilatation  of  the  nares,  the  vocal  cords  are  ab- 
ducted, and  the  intercostal  muscles,  along  with  the  scalenes  and  the 
diaphragm  are  contracting  while  the  muscles  of  the  abdominal  wall  are 
relaxing;  and  all  these  events  occur  at  exactly  the  proper  time  so  as  to 
bring  about  the  most  efficient  opening  up  of  the  thoracic  cavity.  Evi- 
dently there  must  be  some  mechanism  to  insure  this  perfect  control.  This 
is  effected  through  the  nervous  system. 

THE  RESPIRATORY  NERVE  CENTERS 

The  efferent  fibers  to  the  various  groups  of  muscle  originate  in  their 
respective  motor  neurons,  which  in  most  cases  are  situated  in  the  gray 
matter  of  the  spinal  cord.  The  harmonious  action  of  these  motor  neu- 
rons, or  subsidiary  centers,  is  brought  about  by  the  transmission  to  them 
of  impulses  from  a  higher  or  master  center  placed  in  the  medulla  ob- 
longata, the  pathway  of  transmission  between  this  master  center  and  the 
subsidiary  centers  being  in  the  lateral  columns  of  the  spinal  cord. 

The  evidence  that  the  chief  respiratory  center  is  in  the  medulla  is  fur 
nished  by  observing  the  effects  produced  on  the  respiratory  movements 
by  serial  destruction  of  the  cerebrospinal  axis  from  above  downward. 
By  this  method  the  approximate  position  of  the  center  is  found,  its  exact 
location  being  then  determined  by  punctiform  destruction  or  stimulation 
of  the  supposed  locus  of  the  center.  If  we  destroy  the  cerebrum  from 
before  backward,  piece  by  piece,  we  shall  find  that  no  marked  effect  is 
produced  on  the  respirations  until  we  arrive  at  about  the  middle  of  the 
medulla,  when  immediate  paralysis  of  the  respiratory  movements  occurs. 
If  Ave  now  proceed  to  puncture  various  areas  on  the  floor  of  the  fourth 
ventricle  in  another  animal,  we  shall  find  an  area  called  the  noeud  vital, 
located  about  the  tip  of  the  calamus  scriptorius,  destruction  of  which 
causes  immediate  cessation  of  respiration.  It  is  believed  that  the  center 
resides  in  the  group  of  nerve  cells  known  to  neurologists  as  the  fasciculus 
solitarius.     It  is  bilateral. 

327 


::i's 


THE    KKSIMKATIOX 


Tin  subsidiary  centers  are  entirely  dependent  upon  the  master  center 
for  their  harmonious  action,  as  is  shown  by  the  fact  that  if  the  phrenic 
motor  neuron — which  is  situated  in  the  cervical  spinal  cord  between  the 
fourth  and  sixth  spinal  segments — is  isolated  from  the  medulla  by  a 
lateral  hemisection  of  the  cord  just  above  the  fourth  segment  and  by 
mesial  section  of  the  cord  opposite  the  center,  the  corresponding  half  of 
the  diaphragm  no  longer  participates  in  the  inspiratory  act  (see  Fig.  118). 

The  chief  center  on  either  side  of  the  midline  of  the  medulla  is  con- 
nected with  the  motor  neurons  of  both  sides  of  the  spinal  cord,  as  is 
proved  by  the  following  experiment.  When  the  central  end  of  the  vagus 
nerve  is  stimulated,  the  respiratory  center  becomes  excited  and  the  respi- 
rations more  pronounced,  the  participation  of  the  muscles  on  both  sides 
of  the  body  being  equal  in  extent.    If  now  we  bisect  the  medulla  down  the 


Spinal  cord 
-   root5 


Fig.    118. — Diagram   to   show   cuts   required   for   isolation   of   the   phrenic   center. 

midline  and  repeat  the  stimulation  of  one  vagus,  the  muscles  on  both  sides 
will  still  participate  in  the  increased  respiration,  which  they  will  likewise  do 
if  the  cervical  cord  is  bisected  or  hemisected  but  the  medulla  left  intact 
(Fig.  119).  The  simplest  interpretation  of  these  results  is  that  commis- 
sural fibers  connect  both  halves  of  the  respiratory  center  in  the  medulla 
and  that  each  half  is  also  connected  with  the  motor  neurons  of  both  sides 
of  the  spinal  cord.  Often,  especially  in  young  animals,  a  hemisection  of 
the  cord  causes  cessation  of  the  movements  of  the  diaphragm  on  the  same 
side;  but  this  paralyzed  side  at  once  begins  to  contract  again  Avhen  the 
phrenic  of  the  opposite  side  is  cut,  probably  because  the  respiratory 
impulse  descending  from  the  chief  center,  on  finding  its  way  along  the 
motor  center  of  the  same  side  of  the  cord  blocked,  is  forced  to  follow  the 
crossed  path.  The  crossing  in  the  cord  is  believed  to  take  place  at  the 
same  level  as  thai  at  which  the  subsidiary  center  is  located  (W.  T. 
Porter1-). 


CON'TKO!,   OK    'NIK    RESPIRATION 


329 


The  question  now  arises  as  to  how  the  chief  center  functionates.  Is  it 
purely  reflex  in  the  sense  thai  it  depends  for  its  activity  entirely  on  the 
transmission  to  it  of  nervous  impulses  from  elsewhere,  or  is  it  automatic 

in  the  sense  that  it  can  work  independently  of  such  impulses.'  The  an- 
tomaticity  of  the  heart  makes  it  seem  not  improbable  that  the  center 
which  controls  the  co-ordinate  action  of  (lie  respiratory  muscles  would 
also  have  an  inherent  or  automatic  power.  The  activity  of  such  an  auto- 
matic respiratory  center  would,  of  course,  be  subject  to  greal  variation 
as  a  result  of  changes  in  the  composition  of  the  blood  supplying  it.  and 
the  fact  that  it  was  automatic  would  not  remove  it  from  the  influence  of 
nervous  impulses.  Indeed  it  is  possible  to  conceive  of  the  automaticity 
of  the  center  as  being  of  a  low  order,  with  its  normal  functioning 
dependent  upon   afferent    nerve  impulses.      Its  automaticity  might,  then, 


Medulla 


Fig.  119. — Diagram  to  show  certain  positions  in  the  medulla  and  upper  cervical  cord,  when 
sections  may  be  made  without  seriously  disturbing  the  respirations.  Sections  made  separately  will 
not  disturb  the  respiration,  nor  interfere  with  the  effect  of  vagus  stimulation.  If  both  sections 
arc  made  at  once,  however,  breathing  will  be  seriously  interfered  with  on  the  side  01  the 
hemisection,    and    this    side    will    not    respond    to    vagus    stimulation. 

be  merely  a  factor  of  safety  called  into  play   only   when  the  influences 
ordinarily  controlling  the  center  were  for  some  reason  removed. 

The  question  which  at  present  confronts  us,  however,  is  whether  the 
center  may  or  may  not  act  automatically.  Many  experiments  have  been 
undertaken  to  test  this  point,  the  nature  of  all  of  them  depending  upon 
the  isolation  of  the  center  as  completely  as  possible  from  afferent  nerve 
paths.  The  most  successful  experiment  lias  been  performed  as  follows: 
The  influence  of  the  higher  nerve  centers  was  removed  by  cutting  across 
the  peduncles  of  the  cerebrum  or  the  pons.  The  influence  of  afferent  im- 
pulses traveling  up  the  spinal  cord  was  removed  by  completely  severing 
the  spinal  cord  below  the  level  of  the  phrenic  nerves  and  sectioning  all 
the  posterior  or  sensory  spinal  roots  of  the  cervical  cord  above  the  level 
of  this  section.     The  vagi  were  also  cut  to  remove  the  impulses  traveling 


330 


THE   RESPIRATION 


by  them  to  the  respiratory  center.  By  such  an  operation  the  only  lower 
respiratory  neurons  left  intact  are  those  of  the  phrenic  nerve,  so  that  the 
respiratory  movements  that  alone  are  possible  are  those  in  which  the 
diaphragm  participates  and  the  muscles  of  the  alae  nasi  and  larynx.  It 
was  found  that  the  animal  after  the  operation  went  on  respiring,  though 
imperfectly,  and  that  the  respirations  soon  became  more  marked  and 
nsphyxial   in   character,   indicating   that   the   blood   was   not   becoming 


Vagus.X. 


Diaphragm. 

Fig.    120. — Diagram    to    show    where    cuts    are    made    to    isolate    the    chief    respiratory    center    from 

afferent  impulses. 

properly  aerated  and  that  the  chemical  changes  occurring  in  it  were 
acting  directly  on  the  center,  stimulating  it  to  greater  activity.  The 
eonclusion  seems  warranted  that  the  respiratory  center  can  act  auto- 
matically, for  the  only  possible  afferent  nerves  left  in  the  above  prepara- 
tion were  those  carried  to  the  center  by  the  fifth  nerve  (Fig.  120). 

That  the  respiratory  center  is  extraordinarily  sensitive  to  changes  in 
the  composition  of  the  blood  flowing  through  it  is  a  fact  that  has  been 
known  for  a  long  time,  but  it  is  only  within  recent  years  that  the  exact 


THE   CONTROL   OF   THE   RESPIRATION  331 

nature  of  this  control  and  the  remarkable  sensitivity  of  the  center  towards 
it  have  been  thoroughly  established.  We  shall  return  to  this  important 
sub j eel  Later.  Meanwhile  we  shall  proceed  to  examine  the  manner  in 
which  the  center  is  affected  by  sensory  impulses  transmitted  to  it. 

THE  REFLEX  CONTROL  OF  THE  RESPIRATORY  CENTER 

The  afferent  nerve  fibers  going  to  the  respiratory  center  may  conven- 
iently lie  divided  into  two  groups:  those  which  act  on  it  only  occasionally, 
and  those  which  act  on  it  more  or  less  continuously. 

The  Occasionally  Acting  Impulses 

To  the  first  group  belong  afferent  nerves  from  practically  every  part  of 
the  body.  That  impressions  from  the  skin  affect  the  respiratory  center 
is  well  known  by  the  increased  breathing  caused  by  applications  of  cold 
water.  The  influence  of  these  afferent  impulses  is  often  very  marked, 
and  is  frequently  taken  advantage  of  in  stimulating  a  newborn  infant  to 
take  the  first  breath.  Stimulation  of  the  terminations  of  the  fifth  nerve 
in  the  mucous  membrane  of  the  nose,  as  by  inhaling  a  pungent  odor, 
immediately  inhibits  respiration.  To  these  occasionally  acting  afferent 
impulses  may  be  added  the  impulses  that  are  conveyed  to  the  respiratory 
center  from  the  higher  nerve  centers  of  the  cerebrum.  These  impulses 
are  largely  voluntary  in  nature,  and  enable  us  to  hold  our  breath  at  will. 
Some  of  the  cerebral  impulses  are  however  also  involuntary,  their  exist- 
ence being  seen  by  observing  the  respirations  of  an  animal  before  and 
after  sectioning  the  pons  or  peduncles.  The  respirations  for  a  time  at  least 
become  distinctly  affected,  but  they  later  return  with  perfect  regularity. 
They  may  become  very  irregular,  however,  if  the  vagi  as  well  as  the  pons 
are  cut.  Other  experimental  evidence  of  the  existence  of  cerebral  respir- 
atory fibers  is  furnished  by  cerebral  localization  experiments.  During 
stimulation  of  the  cerebral  cortex,  for  example,  a  marked  effect  on  the 
respiratory  movements  is  often  noted. 

Respiratory  rhythm,  unlike  that  of  the  heart,  has  often  to  be  modified 
in  order  that  the  respiratory  mechanism  may  be  used  for  other  purposes 
than  the  ventilation  of  the  lungs.  This  alteration  in  rhythm  may  take 
the  form  of  a  mere  inhibition,  such  as  the  act  of  swallowing;  or  the 
respiration  may  be  altered,  as  in  phonation  and  singing.  More  consid- 
erable alteration  in  the  expiratory  discharge  occurs  in  coughing  and 
sneezing,  and  still  more  in  the  acts  of  micturition,  defecation,  and  parturi- 
tion. AVe  must  conclude  therefore  that  the  rhythmic  stimuli  sent  out 
from  the  respiratory  center  are  so  weak  that  stimuli  from  other  sources 
may  instantly  inhibit  or  change  their  form  at  any  stage  of  the  cycle. 


332  THE    RESPIRATION 

Stimulation  of  the  endings  of  the  glossopharyngeal  nerve  inhibits  res- 
piration, which  explains  the  holding  of  the  breath  that  occurs  in  swal- 
lowing. 

The  Continuously  Acting  Afferent  Impulses 

The  continuously  acting  afferent  impulses  are  transmitted  to  the  chief 
respiratory  center  by  the  vagi  and  their  branches,  the  superior  laryngeal 
nerves.  If  the  vagus  nerves  are  cut  or  their  continuity  severed  by 
freezing  a  portion  of  them,  the  respiratory  movements  become  markedly 
slower.  Evidently,  the  vagus  nerves  in  some  way  hurry  up  the  respira- 
tory movements.  Again,  if  the  central  end  of  either  vagus  is  stimu- 
lated with  the  ordinary  interrupted  faradic  current,  a  profound  effect 
on  the  respiratory  movements  is  usually  observed.  This  effect  is  how- 
ever not  strictly  predictable.  Usually  there  is  a  quickening  of  respira- 
tion, and  if  the  stimulus  is  a  strong  one,  there  may  be  a  standstill  of  the 
thorax  in  the  inspiratory  position.  On  the  other  hand,  if  the  central 
end  of  the  nerve  is  stimulated  with  other  types  of  stimuli;  as  by  slow, 
weak  faradic  shocks  or  by  the  stimulus  produced  by  the  closure  of  an 
ascending  voltaic  current,  the  effect  may  be  to  stimulate  expiration 
rather  than  inspiration.  Such  results  would  seem  to  indicate  that  the 
vagus  contains  two  hinds  of  afferent  fibers  to  the  respiratory  center,  one 
kind  stimulating  inspiration,  the  other,  stimulating  expiration. 

Supposing  that  such  fibers  exist,  the  next  question  is,  how  do  they 
become  stimulated  at  their  terminations  in  the  lungs?  The  most  nat- 
ural assumption  is  that  the  mechanical  distention  and  collapse  of  the 
alveoli  which  occurs  with  each  respiratory  act,  serves  as  the  stimulus — 
an  hypothesis  to  which  support  is  offered  by  the  observation  that,  when 
air  is  blown  into  the  lungs  so  as  to  distend  the  alveoli,  the  animal  im- 
mediately makes  a  forced  expiratory  movement,  whereas  when  the  air 
is  sucked  out,  the  thorax  assumes  the  inspiratory  position. 

Of  the  many  methods  that  have  been  employed  to  produce  disten- 
tion of  the  alveoli,  the  best  is  undoubtedly  that  recently  employed  by 
Haldane  and  Boothby.13  The  person  or  animal  is  made  to  respire  through 
a  tube  in  which  is  inserted  a  three-way  stopcock,  which  communicates 
either  with  the  outside  air  or  with  a  side-tube  leading  to  a  spirometer 
or  bag  containing  air  under  slight  pressure,  so  that  when  the  stopcock 
is  turned  breathing  takes  place  against  a  definite  positive  pressure. 
Such  a  method  is  obviously  much  more  physiologic  than  one  in  "which 
the  air-tube  is  suddenly  clamped  at  the  end  of  inspiration  and  the  lungs 
left  in  a  distended  condition. 

The  term  used  to  designate  the  cessation  of  breathing  is  called  apnea. 
The  extent   to  which  it  occurs  varies  very  considerably  in  different  an- 


THE    CONTROL    OP    THE    RESPIRATION  333 

[mals  and,  in  the  case  of  man,  in  different  individuals.  Tims,  when  a 
man  is  made  suddenly  i<>  breathe  into  compressed  air,  the  apnea  often 
lasts  for  ahoid  half  a  minute,  the  pause  being  then  broken  by  ;i  deep  ex- 
piration followed  by  a  further  pause,  thou  again  an  expiration,  and  so 
on  with  progressively  shorter  pauses.  Disregarding  Cor  the  presenl 
any  influences  which  changes  in  the  composition  of  the  air  in  the  lungs 
or  of  the  gases  in  the  blood  mighl  have  in  producing  the  apnea,  we  maj 
consider  the  possibility  that  it  is  the  result  of  afferent  fibers  in  the 
vagus.  This  is  an  old  view,  hut  the  most  recent  experimental  evidence 
does  no1  lend  support  to  it.  It  was  shown  by  Boothhy  and  Berry,14  for 
example,  that  a  similar  apnea,  though  indeed  of  shorter  duration,  could 
he  produced  in  dogs  in  which  the  pulmonary  branches  of  both  vagus 
nerves  had  been  severed  two  months  previously.  The  apnea  is,  there- 
fore, not  a  reflex  of  the  vagus,  and  must  he  interpreted  as  due  to  nerv- 
ous impulses  passing  to  the  respiratory  center  from  some  other  part  of 
the  nervous  system,  perhaps  from  centers  higher  up,  or  to  stimuli  trans- 
mitted to  the  respiratory  center  possibly  through  afferent  fibers  in  the 
respiratory  muscles. 

The  formerly  very  popular  theory  that  respiration  is  controlled  au- 
tomatically by  alternate  distention  and  collapse  of  the  alveoli,  acting 
through  the  afferent  fibers  of  the  vagus  nerve  on  the  respiratory  center 
in  such  a  way  as  to  bring  the  opposite  act  with  each  expiration  and 
inspiration,  must,  therefore,  be  abandoned.  But  we  can  not  deny  that 
the  vagus  plays  a  most  important  role  in  the  control  of  the  function  of 
the  respiratory  center,  for  apart  from  the  effect  which  Ave  have  seen  to 
follow  the  severence  of  continuity  of  the  nerve,  there  is  the  important 
observation  of  Alcock  and  others1"'  that  when  nonpolarizable  electrodes 
are  placed  on  the  vagus  nerve  and  connected  with  a  galvanometer,  a 
current  of  action  occurs  toward  the  end  of  each  inspiration  in  quiet 
breathing;  and  when  the  respirations  are  forced,  a  current  of  action 
appears  during  both  inspiration  and  expiration.  Another  reason  for 
believing  that  the  vagi  have  some  important  function  to  perform  in  con- 
nection with  the  control  of  respiration  is  the  fact,  observed  by  F.  H.  Scott, lfi 
that  in  an  intact  animal,  when  atmospheres  containing  increasing  percent- 
ages of  carbon  dioxide  are  respired,  the  respirations  become  both  deeper 
and  (pucker,  whereas  in  one  whose  vagi  have  been  cut  the  carbon  diox- 
ide causes  only  a  deepening  of  the  respirations.  From  this  result  it 
would  appear  that  the  vagi  exert  an  influence  on  the  rate  of  the  respira- 
tions but  not  on  their  depth,  this  effect,  as  we  shall  see  later,  being  de- 
pendent primarily  on  changes  in  the  composition  of  the  blood  supplying 
the  respiratory  center.  11  is  probable  that  both  controlling  agencies  act 
together,  the   one  serving  to  maintain   the  center  in   a   proper  state   of 


334  THE   RESPIRATION 

excitability,  and  being  active  to  a  greater  or  less  extent  all  the  time; 
while  the  other  acts  only  occasionally  on  the  "tuned  up"  center.  There 
is,  of  course,  no  doubt  that  it  is  through  the  nerves  that  the  occasional 
alterations  of  respiration  occur.  They  appear  also  to  have  a  certain 
influence  on  the  rhythm,  for  Stewart,  Pike  and  Guthrie17  observed  that, 
after  resuscitation  from  acute  brain  anemia,  the  respirations  when  they 
returned  were  of  the  same  rhythm  as  that  of  the  artificial  respirations 
employed  during  the  resuscitation. 

The  usually  accepted  hypothesis  as  to  the  mechanism  by  which  the 
nerve  impulses  hasten  the  respiratory  movements  is  that  an  afferent 
impulse  is  transmitted  to  the  respiratory  center  towards  the  end  of  each 
inspiration,  which  has  the  effect  of  inhibiting  the  inspiratory  discharge 
from  the  center  and  thus  cutting  short  the  act  of  inspiration  so  that  ex- 
piration automatically  supervenes.  This  explanation  is  in  agreement 
with  the  fact  that  quiet  inspiration  involves  activity  on  the  part  of  the 
respiratory  muscles,  whereas  expiration  is  usually  almost  entirely  pas- 
sive, being  due  to  the  return  to  a  resting  position  of  the  stretched  and 
displaced  structures.  On  the  other  hand,  in  forced  respiration  and  in 
certain  animals  under  normal  conditions,  expiration  becomes  active,  in 
which  event  a  current  of  action  becomes  evident  in  the  vagus  nerve  dur- 
ing the  expiratory  phase. 

The  superior  laryngeal  branch  of  the  vagus  should  really  be  classified 
as  one  of  those  nerves  that  have  an  occasional  influence  on  the  respiratory 
center,  its  particular  function  being  in  connection  with  the  act  of  cough- 
ing. When  a  foreign  body  irritates  the  mucous  membrane  of  the  larynx, 
the  nerve  fibers  transmit  impulses  to  the  respiratory  center  which  ex- 
cite a  violent  expiration  and  at  the  same  time  cause  the  glottis  to  close. 
The  closure  of  the  glottis  lasts,  however,  only  during  the  first  part  of 
the  expiration ;  it  then  opens,  with  the  result  that  the  sudden  release  of 
intrapulmonic  pressure  causes  the  expulsion  of  the  foreign  substance 
in  the  air  passages. 


CHAPTER  XXXVIII 

THE  CONTROL  OF  RESPIRATION  (Cont'd) 

THE  HORMONE   CONTROL  OF  THE  RESPIRATORY   CENTER 

Just  as  the  rhythmical  activity  of  the  heart  is  readily  influenced  by 
changes  in  the  composition  of  the  blood  supplying  it,  so  also  is  that  of 
the  respiratory  center.  In  the  case  of  the  heart  it  is  the  cations — cal- 
cium, potassium  and  sodium — that  have  the  most  pronounced  effect, 
•whereas  in  the  case  of  the  respiratory  center  it  is  largely  the  relative  con- 
centration of  hydrogen  and  hydroxyl  ions — the  H-ion  concentration 
(CH)  of  the  blood.  This  influence  can  be  shown  in  a  general  way  by 
injecting  acid  or  alkaline  solutions  into  the  peripheral  end  of  the  carotid 
artery  of  an  anesthetized  animal,  or  better  still  of  one  that  has  been 
decerebrated.  Acid  injections  stimulate  the  respiratory  activity;  alka- 
line injections  tend  to  depress  it.  "When  the  acid  or  alkaline  solutions 
are  injected  intravenously  in  other  parts  of  the  body,  so  that  they  be- 
come thoroughly  mixed  with  the  blood  before  the  respiratory  center  is 
reached,  the  effects  are  not  nearly  so  pronounced,  because  the  buffer  in- 
fluence of  the  blood  has  time  to  develop  (see  page  36). 

From  the  results  of  such  injection  experiments,  however,  one  could 
not  draw  the  conclusion  that  under  normal  conditions  the  activity  of 
the  respiratory  center  is  affected  by  measurable  changes  in  CH  of  the 
blood,  for,  as  we  have  seen,  constancy  of  CH  is  one  of  the  most  remark- 
able properties  of  the  animal  fluids.  To  justify  the  conclusion  that  the 
respiratory  center  is  affected  by  changes  in  CH,  it  is  necessary  to  observe 
the  behavior  of  some  easily  measurable  acid  or  alkaline  constituent  of 
the  blood  that  undergoes  changes  in  amount  that  are  proportional  to  an 
alteration  in  CH.  In  order  to  understand  what  this  acid  or  basic 
substance  may  be,  it  will  be  advisable  to  recapitulate  the  main  factors 
concerned  in  maintaining  CH  at  a  constant  level.  This  value  is  obviously 
dependent  upon  the  balance  between  jbasic  and  acid  substances,  so  that 
any  variations  which  it  undergoes  must  be  caused  by  changes  in  the 
relative  amount  of  one  of  these.  Changes  in  base  may  occur,  exoge- 
nously,  by  altering  the  alkali  content  of  the  food,  or,  endogenously,  in 
various  ways  but  particularly  by  variations  in  the  amount  of  ammonia 
produced  during  the  course  of  metabolism  of  protein.  Thus,  when  sud- 
den demands  are  made  by  the  organism  for  an  increased  amount  of  base, 

335 


336  THE    RESPIRATION 

the  amino  groups— split  off  from  the  amino  bodies — become  converted 
into  ammonia  instead  of  into  the  neutral  substance,  urea.  But  the  chief 
variations  seem  to  concern  acids  rather  than  the  basic  substances.  These 
acids  may  be  divided  into  three  groups:  fixed  inorganic  acids,  represented 
by  phosphoric;  fixed  organic  acids,  represented  by  lactic;  and  volatile 
acids,  represented  by  carbon  dioxide.  Of  these  three  groups,  the  first 
shows  the  least  tendency  to  change,  and  the  third,  the  greatest.  Changes 
in  the  second  group  (fixed  organic  acids)  are  effected  partly  by  excretion 
through  the  urine  and  partly  by  oxidation  into  volatile  acid.  The  sud- 
den and  rapid  changes  in  the  third  group  are  brought  about  by  the  dif- 
fusion of  the  C02  of  the  blood  into  the  alveolar  air.  Gross  changes  in 
the  acid  content  of  the  blood  are  therefore  mainly  effected  through  al- 
teration in  the  excretion  of  the  fixed  acids,  whereas  sudden  changes  are 
effected  by  excretion  of  the  volatile  acid.  It  is  important  to  note  here 
that  the  fixed  organic  acids  do  not  participate  to  any  great  extent  in 
the  makeup  of  the  acid  content  of  normal  blood:  they  appear  only  under 
unusual  conditions,  as  in  dyspnea.  The  variations  in  CH  that  ordinarily 
affect  the  activity  of  the  respiratory  center  are  therefore  dependent 
upon  changes  in  the  volatile  acid,  a  direct  measure  of  which  is  found 
in  the  tension  of  ('(K  in  the  blood.  The  correlation  between  CH  of  the 
blood  and  respiratory  activity  must  be  a  very  close  one  if  CH  is  to  be 
maintained. 

The  Laws  of  Gases. — Tn  order  to  understand  the  principles  upon  which 
alterations  in  C02  tension  are  dependent,  it  will  be  necessary  for  us  to 
review  briefly  some  of  the  gas  hues.  Among  these  laws  the  first  in  im- 
portance is  the  law  of  pressure,  which  states  that,  other  things  being 
equal,  the  pressure  of  a  gas  is  inversely  proportional  to  its  volume;  if 
a  gas  occupying  a  certain  volume  is  compressed  by  a  pump  so  that  it  oc- 
cupies one-half  of  its  previous  volume,  its  pressure  will  become  doubled. 
The  second  is  the  laic  of  partial  pressure,  which  states  that  the  partial 
pressure  of  a  gas  in  a  mixture  of  gases,  having  no  action  on  one  another, 
is  equal  to  that  which  this  particular  gas  would  exert  did  it  alone  oc- 
cupy the  space  occupied  by  the  mixture.  Thus,  atmospheric  air  consists 
roughly  of  70  volumes  per  cent  of  nitrogen  and  21  of  oxygen;  the  par- 

21 

tial  pressure   of  the   oxygen    is  therefore   equal    to  y;^vX  "^  mni-      ^^- 

this  last  figure  being'  the  barometric  pressure  of  air  at  sea  level.  The 
third  is  the  law  of  solution  of  <i«s<  s,  which  is  to  the  effect  that  the  amount 
of  gas  which  goes  into  solution  in  a  liquid  having  no  chemical  attraction 
for  the  gas,  is  proportional  to  the  partial  pressure  of  gas.  If  water  is 
exposed  to  air,  the  amount  of  oxygen  which  it  dissolves  will  be  the  same 
as  if  the  water  had  been  exposed  to  oxygen  at  a  pressure  equal  to  that 


THE    CONTROL   OP    THE    RESPIRATION  3.">7 

of  llic  partial  pressure  which  il  produces  in  air.  The  same  will  be 
the  case  with  the  nitrogen  of  the  air.  The  actual  amount  of  gas  which 
becomes  dissolved  in  the  fluid,  pressure  and  temperature  being  constant, 
depends  partly  on  the  nature  of  the  gas  and  partly  on  the  nature  of  the 
fluid.  For  example,  the  solubility  of  oxygen  in  water  is  considerably 
different  from  that  in  a  neutral  oil;  or,  taking  the  same  solvent,  nitro- 
gen and  C02  do  not  dissolve  to  the  same  extent  in  water.  Tt  becomes 
necessary,  therefore,  in  calculating  what  amount  of  a  particular  gas 
will  dissolve1  in  a  particular  fluid  to  use  a  figure  known  as  the  coefficient 
of  solubility  of  the  gas — that  is,  the  amount  of  gas  taken  up  by  a  unit 
volume  of  fluid  at  standard  temperature  and  pressure;  for  example,  to 
say  thai  the  coefficient  of  absorption  of  nitrogen  in  water  at  0°  C.  is 
0.0239  means  that,  at  this  temperature  and  at  normal  barometric  pres- 
sure, 1  c.c.  of  water  Avill  dissolve  0.0230  e.e.  of  nitrogen  when  exposed  to 
a  pure  atmosphere  of  this  gas.  Obviously,  then,  if  water  were  exposed 
fo  79  per  cent  of  an  atmosphere  of  nitrogen   (as  in  air)  the  amount  which 

79 
would  become  dissolved  in  each  e.e.  would  be  Ynnx  0-^239  =  0.0189  c.c. 

In  solutions  containing  no  chemical  substances  with  which  the  gas  can 
enter  into  combination,  it  is  evident  that  the  tension  of  the  gas  will  be 
proportional  to  the  amount  of  gas  that  can  be  displaced  or  pumped  out 
from  the  fluid.  On  the  other  hand,  when  a  chemical  compound  is  formed, 
the  combined  gas  will  exercise  no  direct  influence  on  the  tension,  so  that 
this  Avill  be  independent  of  the  amount;  in  such  cases  separate  methods 
will  have  to  he  used  for  the  determination  of  amount  and  tension.  Let 
us  take  the  case  of  pure  water  exposed  to  an  atmosphere  of  C02:  the 
amount  of  CO.,  which  goes  into  solution  will  depend  entirely  on  the 
pressure.  If  a  trace  of  alkali  is  dissolved  in  the  water,  however,  some 
of  the  C02  will  become  combined  to  form  carbonate,  so  that  a  much 
larger  quantity  of  C02  will  be  displaceable  from  the  solution  (as  by 
adding  a  mineral  acid  to  it)  than  corresponds  to  the  tension  of  C02  in 
the  atmosphere  surrounding  it.  Since  blood  contains  alkali  the  condi- 
tions arc  analogous  with  those  of  a  weak  alkaline  solution. 

The  Tension  of  CO.,  and  O,  in  the  Arterial  Blood. — If  we  were  to 
pass  blood  at  body  temperature  in  a  very  thin  film  over  the  walls  of  a 
confined  space  containing  a  mixture  of  gases  one  of  which  was  C02,  it 
is  evident  that  the  percentage  of  C02  in  the  atmosphere  contained  in 
this  space  would  remain  unchanged  only  when  the  tension  of  this  gas  in 
the  blood  was  the  same  as  that  in  the  confined  atmosphere.  If,  on  the 
other  hand,  the  tension  of  C02  in  the  blood  should  correspond  to  a  per- 
centage that  is  higher  than  that  in  the  atmosphere,  then  C02  would  dif- 
fuse from  the  blood,  and  at  the  end  of  the  experiment  an  analysis  of  the 


338 


THE    RESPIRATION 


atmosphere  in  the  space  would  show  that  the  C02  percentage  had  been 
raised.  If  the  blood  contained  a  lower  tension  than  that  corresponding 
to  the  percentage  of  C02  in  the  space,  some  of  the  C02  would  diffuse 
into  the  blood,  and  its  percentage  in  the  atmosphere  Avould  be  lowered. 
By  successively  exposing  blood  to  gas  mixtures  that  contain  slightly 
different  percentages  of  C02,  we  should  ultimately  find  one  with  which 
the  free  C02  in  the  blood  was  in  perfect  equilibrium,  and  we  should  be 
able  to  state  that  the  tension  of  this  gas  in  the  blood  was  equal  to  a 
certain  percentage  in  the  atmosphere  surrounding  the  blood  (see  Fig. 
121). 

Many  forms  of  apparatus  based  on  the  above  principle  have  been  in- 
vented for  the  examination  of  the  tension  of  the  gases  in  the  blood. 
The  most  accurate  is  that  devised  by  Krogh,18  the  principle  of  which 


co. 


<.°/„a1  start 


^^^^^>^^a«a»g»>^^^^^-^^^^> 


S.S  ftt  it  art 
C0a     5.1  ».Te.v>d 


ZSS^gsg  SSgSggggjgaS^^iS^gSSeSSgg 


CO,        S.ti    *T  start 
S.TS   »t  eo.1 


IT 


-v  ■^&2&^^&as&se^^&. ';//s/sy'/^ysi*s4''i*r 


Fig.    121. — Diagram    to    show    principle    for    measurement    of    the    tension    of    CO2    in    blood. 
CO2    tension    of    blood    is    supposed    to    be    5.75. 


The 


differs  slightly  from  that  just  described  in  that  a  bubble  of  air  is 
exposed  to  a  relatively  large  quantity  of  blood,  so  that  after  a  time 
actual  equilibrium  of  gas  tension  becomes  established  between  the  bub- 
ble and  the  gases  of  the  blood.  This  apparatus  is  shown  in  Figs.  122 
and  123.  It  consists  of  a  graduated  tube  of  narrow  bore  sur- 
rounded by  a  water  jacket.  To  the  upper  end  of  the  graduated  tube 
a  small  syringe  is  attached.  The  lower  end  of  the  graduated  tube  ex- 
pands into  a  thistle-shaped  bulb,  closed  below  by  a  cork,  through  which 
is  inserted  a  tube  (inflow  tube)  ending  near  the  top  of  the  bulb  in  a 
fine  opening  and  connected  outside  with  an  artery.  An  outflow  tube  is 
also  connected  with  the  thistle-shaped  bulb. 

At  the  beginning  of  the  experiment  the  thistle-shaped  bulb  and  the 
graduated  tube  are  filled  with  physiologic  saline.  By  means  of  the 
syringe  a  small  bubble  of  air  is  then  introduced,  so  that  it  lies  at  the 


Tin:   CONTROli   ok   Tin:   RESPIRATION 


339 


junction  of  the  thistle  shaped  bulb  and  the  graduated  tube.    As  the  1>1 1 

is  allowed  to  enter  through  the  inflow  tube,  it  is  ejected  in  a  fine  stream 
around  the  bubble  of  air,  which  moves  about  in  the  stream.  The  blood 
displaces  the  saline  out  of  the  bulb  into  the  side  tube.  After  the  bub- 
ble has  been  subjected  to  the  influence  of  the  blond  for  some  minutes, 
the  gases  in  it  come  into  perfect  equilibrium  with  those  in  the  blood. 
The  percentage  of  Q2  and  C02  in  the  bubble  will  therefore  correspond 
to  the  tension  of  these  gases  in  the  blood.  The  analysis  is  effected  by 
drawing  the  bubble  into  the  graduated  tube  by  means  of  the  syringe, 


Fig.    12: 


Fig.   123. 


Fig.  122. — The  gas  analysis  pipette  for  the  microtonometer  shown  in  Fig.  123.  For  description 
see   context.      (From   A.    Krogh.) 

Fig.  123. — Microtonometer,  to  be  inserted  into  a  blood  vesseb  The  small  circle  represents  the 
bubble  of  air.     For  further  description  see  context.      (From  A.   Krogh.) 

measuring  its  capacity,  transferring  it  into  a  bulb  containing  KOH, 
which  absorbs  the  C02,  then  taking  it  back  into  the  capillary  tube  and 
again  measuring.  The  shrinkage  obviously  corresponds  to  the  amount 
of  C02.  The  bubble  is  then  transferred  into  potassium  pyrogallate  solu- 
tion, where  the  02  is  absorbed.* 

The  Tension  of  C02  and  02  in  Alveolar  Air. — Having  seen  how  we 
may  determine  the  tension  of  the  gases  in  blood,  we  must  now  consider 


*Since  the  above  was  written,  a  more  efficient    tonometer  devised   by   the   late   T.    G.    Brodie   has 
been  described  by  O'Sullivan  (Am.  Jour.  Physiol.,  Sept.,  1918). 


:J40 


THE    RESPIRATION 


the  method  by  which  the  tensions  of  these  Liases  in  alveolar  air  can  be 

determined.  The  simplest  and  until  recently  the  most  accurate  method 
is  that  of  Haldane  and  Priestley.19  This  consists  in  having  an  individual, 
with  his  nostrils  clamped,  breathe  quietly  through  a  piece  of  hose  pipe 
about  a  meter  long,  which  has  at  the  mouth  end  a  short  side-tube  lead- 
ing to  an  evacuated  gas-sampling  bulb  of  about  50  e.c.  capacity.*  After 
the  subject  has  become  accustomed  to  breathing  through  the  tube,  he 
is  asked  to  make  a  forced  expiration  and  at  the  end  of  it  to  close  the 
mouthpiece  with  his  tongue.  At  this  moment  the  operator  opens  the 
tap  of  the  sampling  tube,  allowing  the  air  from  the  tubing  through 
which  the  individual  has  made  the  forced  expiration  to  rush  in  and  fill 
it.  This  sample  represents  the  air  from  the  alveoli  (see  page  302),  and 
is  analyzed  for  percentages  of  ('().,  and  02.  Since  each  normal  inspira- 
tion dilutes  the  alveolar  air  somewhat,  it  is  necessary,  for  constant  re- 


Fig.     124. — Apparatus    for    collection    of    a    sample    of    alveolar    air    by     Ilalrlane's    method.       It    is 
better  to  use  a  mouthpiece  than  a   mask. 

suits,  to  make  two  analyses  of  alveolar  air  from  each  subject,  one  taken 
at  the  end  of  a  normal  inspiration  and  the  other  at  the  end  of  normal 
expiration.  The  average  of  the  two  results  is  taken  as  the  composition 
of  the  alveolar  air. 

On  account  of  the  difficulty  in  securing  intelligent  cooperation  in  the 
application  of  this  method,  particularly  with  children,  others  have  been 
deviled.  One  of  the  simplest  is  that  of  Fridericia,  which  is  a  modifica 
tion  of  the  Haldane-Priestley  method,  the  apparatus  for  which  is  shown 
in  the  figure  (Fig.  125),  and  the  manipulation  of  which  is  outlined  in 
the  legend.  Another  is  to  take  a  mixed  sample  of  the  very  last  portion 
of  several  normal  expirations.  On  account  of  the  extended  use  which  is 
being  made  of  measurements  of  alveolar  air  composition,  both   in  lab- 

*In  place  of  the  gas  sampling  tube  it  is  much  more  convenient  am!  equally  accurate  to  employ  one 
of  the  modern  ground  glass  piston  syringes  (l.uer).  The  piston  should,  of  course,  be  well  smeared 
with  a  good  mineral  grease. 


THE   CONTROL   OF   THE   RESPIRATION 


341 


Fig.  125. -  -FriiU-ricia's  apparatus  for  measuring  the  COs  in  alveolar  air.  The  person  expires 
forcibly  through  the  tube  with  the  stopcocks  as  in  I.  A  is  closed  and  the  tube  placed  in  water  to 
cool  the  air,  after  which  B  is  turned  as  in  II.  The  entrapped  column  of  air  equals  100  c.c.  A 
solution  of  caustic  alkali  is  now  sucked  into  C  with  stopcocks  as  in  II.  B  is  then  turned  as  in 
I  but  with  A  still  closed,  and  the  alkali  solution  allowed  to  enter  b,  after  which  B  is  turned  oft, 
the  excess  of  alkali  solution  in  C  allowed  to  run  out  and  the  burette  shaken.  The  burette  is 
then  submersed  up  to  a  in  a  cylinder  of  water,  with  B  as  in  III.  After  allowing  for  cooling, 
the   level   at   which   the   water   stands   gives   the   per  cent   of  CO^. 


iH-7         %    o2 

in  inspired 
air 


(30    to 


20       30      W 


Fig.  126. — Curves  to  show  the  relationship  between  the  02  and  COa  tensions  in  alveolar  air 
(dotted  lines)  and  arterial  blood  (continuous  lines).  It  will  be  observed  that  the  tension  of  C02 
in  blood  is  slightly  above  that  in  alveolar  air,  but  that  the  reverse  relationship  obtains  for  02.  In 
the  upper  part  of  the  curve  the  02  tension  in  the  alveolar  air  was  experimentally  altered,  causing 
a  corresponding  alteration  in  the  62  tension  of  the  blood.  This  result  is  of  practical  significance 
in   connection   with   02   alterations   in   gas   poisoning,   pneumonia,    etc.      (From    A.    and    M.    KroghJ 


342 


THE    RESPIRATION 


oratory  and  in  clinical  work,  a  special  chapter  has  been  devoted  to  the 
subject,  giving  in  detail  the  more  recent  methods  devised  by  R.  G.  Pearce. 

Lastly,  it  should  be  noted  that  several  observers  believe  that  a  more 
reliable  estimate  of  the  alveolar  tension  of  C02  (and  of  02)  can  be  made 
by  analyzing  a  sample  of  ordinary  expired  air  and  calculating  the  per- 
centages of  C02  and  02  in  the  alveolar  air  by  allowing  a  constant  dead- 
space  capacity  of  140  c.c.  (Krogh,  etc.). 

If  we  compare  the  C02  tension  of  arterial  blood,  as  measured  by  the 
Krogh  method,  with  that  of  alveolar  air,  we  shall  find  that  there  is  a 
remarkable  correspondence,  indicating,  therefore,  that,  when  the  arterial 


tfispi. 


•miair 


220 


Fig.    127. — Same  as  Fig.    126,   except  that  in  this  case  the  tension  of  COn   in   the  alveolar  air  was 
experimentally   altered.      (From   A.   and   M.    Krogh.) 

blood  leaves  the  alveoli,  its  partial  pressure  or  tension  of  C02  is  exactly 
equal  to  that  in  the  alveolar  air.  This  is  shown  in  the  accompanying 
curves  of  experiments  performed  by  Krogh.  The  dotted  line  in  these 
curves  represents  the  tension  of  CO,  or  02  in  alveolar  air,  and  the  con- 
tinuous line,  these  tensions  in  arterial  blood.  Close  correspondence 
will  be  observed  between  the  C02  curves  even  when  sudden  changes  in 
alveolar  C02  were  induced  by  artificial  means.  In  the  case  of  the  02 
tensions,  however,  that  of  the  blood  is  always  lower  than  that  of  the 
alveolar  air,  the  differences  being  especially  marked  when  the  02  ten- 
sion in  the  alveoli  is  raised  (Figs.  126  and  127). 

Tension  of  C02  in  Venous  Blood. — If  we  examine  the  C02  tension  of 
the  venous  blood  coming  to  the  lungs,  we  shall  find  that  it  is  distinctly 


TIIE    CONTROL   OF    THE    RESPIRATION  343 

higher  than  that  in  the  alveolar  air.  The  earliest  method  for  measuring 
it  consisted  in  passing  a  lung  catheter  into  the  right  bronchus  and  then 
blocking  the  passage  above  the  open  end  of  the  catheter  by  inflating  a 
rubber  collar  or  ampulla.  The  renewal  of  air  in  the  right  lung  is  thereby 
prevented,  and  a  sample  of  the  stagnant  air  can  be  removed  and  analyzed. 
In  such  a  case,  however,  the  blood  will  have  circulated  several  times 
round  the  body,  and  with  only  one  lung  operating  the  risk  is  incurred 
that  more  C02  is  being  discharged  into  the  blocked  lung  than  cor- 
responds to  the  tension  of  C02  of  venous  blood  under  normal  conditions. 

Much  more  practical  methods  are  those  of  Haldane,  Yandell  Hender- 
son and  R.  G.  Pearce,  which  are  much  the  same  in  principle.  In  Pearce 's 
method,  the  person  first  of  all  inspires  from  a  gas  meter  containing  a 
gaseous  mixture  with  about  10  per  cent  of  C02.  Immediately  after  fill- 
ing the  lungs,  he  makes  a  rapid  forced  expiration  into  a  tube  provided 
with  a  valve  having  four  openings.  This  valve  is  turned  through  a 
complete  circuit  during  the  expiration,  so  that  four  fractions  of  the  ex- 
pired air  can  be  collected  in  rubber  bags  connected  with  side  tubes 
opening  opposite  the  four  openings  in  the  valve.  The  first  fraction  will 
contain  a  little  less  than  10  per  cent  C02,  the  second  distinctly  less, 
while  the  fourth  will  contain  the  same  as  the  third,  indicating  that  equi- 
librium between  the  C02  of  the  alveolar  air  and  the  blood  must  have  been 
attained.  This  figure  therefore  gives  us  the  tension  of  C02  in  the  venous 
blood  of  the  lungs.  In  Henderson's  method  the  rebreathing  is  per- 
formed into  gas  receivers  containing  6  per  cent  C02. 

These  results  then  indicate  that  the  whole  process  by  which  C02  is 
exchanged  in  the  lungs  is  dependent  on  the  law  of  gas  diffusion ;  the  gas 
diffuses  from  a  place  of  lower  to  a  place  of  higher  pressure,  and  does 
so  until  equilibrium  is  attained. 


CHAPTER  XXXIX 

THE  CONTROL  OF  RESPIRATION   (Cont'd) 

THE  ESTIMATION  OF  ALVEOLAR  GASES 

By  R,  G.  Pearce,  B.A.,  M.D. 

Methods  such  as  that  of  Haldane  and  Priestley,  which  calculate  the 
mean  percentage  composition  of  the  alveolar  air  by  analysis  of  a  sample 
taken  from  the  end  of  a  prolonged  forced  expiration,  give  values  which 
are  too  high  for  C02  and  too  low  for  02.  There  are  several  reasons 
for  this:  (1)  In  the  time  taken  for  the  prolonged  deep  expiration  an 
appreciable  amount  of  C02  will  be  given  off  by  the  blood  to  the  alveolar 
air,  and  oxygen  will  be  absorbed — that  is,  the  sample  will  not  contain 
the  same  percentages  of  C02  and  02  at  different  stages  of  expiration. 
{2)  The  portion  of  the  tidal  air  vdiieh  reaches  the  alveoli  dilutes  the 
alveolar  air  and  thus  causes  the  amount  of  C02  given  off  by  the  blood  to 
vary  during  the  different  phases  of  respiration.  If  we  bear  in  mind  that 
the  tensions  of  C02  in  the  alveolar  air  and  in  the  blood  leaving  the  lungs 
are  always  the  same  (page  343),  and  that  the  entire  fall  in  ('<),  tension 
in  the  alveolar  air  occurs  during  inspiration,  then  it  is  clear  that  the 
blood  in  the  pulmonary  capillaries  must  have  a  maximum  tension  and 
load  of  C02  at  the  end  of  expiration,  and  a  minimum  tension  and  load 
of  C02  at  the  end  of  inspiration.  Accordingly,  the  average  of  the  per- 
centage of  C02  and  02  at  the  end  of  inspiration  and  expiration,  as  de- 
termined by  the  Haldane-Priestley  method  or  by  any  of  its  modifications, 
must  fail  to  give  the  correct  mean  tension  of  these  gases  in  the  alveolar 
air  during  expiration.  The  error  which  makes  the  CO,  higher  .than  it 
should  be,  makes  the  percentage  of  02  less  than  it  should  be.  These  in- 
fluences taken  along  with  the  fact,  which  will  be  shown  later,  that  the 
evolution  of  C02  from  the  blood  is  relatively  more  rapid  at  low  than  at 
high  tension  of  C02,  indicates  that  the  blood  in  the  pulmonary  capil- 
laries during  inspiration  must  contribute  a  greater  part  of  the  C02 
excreted  during  a  respiratory  cycle  than  that  in  the  pulmonary  capil- 
laries during  expiration,  and  moreover  that  a  greater  part  of  the  CO., 
excreted  must  be  evolved  at  a  tension  which  is  below  the  mean  tension 
of  the  C02  present  in  the  entire  time  of  the  expiration.  We  conclude, 
therefore,  that  the  average  tension  of  C02  in  the  alveolar  air,  determined 

Mi 


THE    CONTROL    OP    THE    RESPIRATION  345 

by  the  actual  tension  under  which  the  gas  is  evolved  from  the  blood,  is 
less  than  ilic  average  tension  of  C02  in  the  alveolar  air  » 1 1 1 1  i 1 1 ir  the  time 
of  a  respiratory  cycle. 

In  the  ease  of  Oa  the  conditions  arc  different.  While  the  diluting 
effect  of  the  alveolar  tidal  air  is  marked  in  altering  the  amount  of  CO 
given  off  during  the  different  phases  of  a  respiration,  ii  ean  have  little 
influence  on  the  amount  of  02  taken  up  by  the  blood  under  uormal  con- 
ditions. This  is  evident  from  a  study  of  the  dissociation  curve  of  hemo- 
globin (page  383),  which  shows  that  at  tensions  above  65  nun.  Hi:"  the 
hemoglobin  is  practically  saturated  with  02.  Since  the  tension  of  0 
in  the  alveolar  air  under  normal  conditions  is  greater  than  65  mm. 
'i.">-100  mm.),  the  rate  of  absorption  of  <>.  must  he  practically  maximal 
during  the  respiratory  cycle — that  is.  it  will  not  change  at  different 
phases  of  it. 

While  the  relationship  of  the  alveolar  gases  is  continually  changing 
at  different  stages  of  the  respiratory  cycle,  their  mean  relationship  for 
periods  including  several  respirations  or  for  complete  respirations  is 
more  or  less  constant,  being  controlled  by  the  type  of  the  metabolism, 
and  mathematically  expressed  by  the  respiratory  quotient  (page  547 1. 
The  average  relative  percentages  of  the  two  gases  in  the  alveolar  air 
must  therefore  he  the  same  as  in  the  tidal  air.  In  the  alveolar  air  col- 
lected by  the  Haldane  method,  however,  the  above  factors  cause  the 
respiratory  quotient  to  he  less  than  that  in  the  tidal  air. 

These  points  have  been  insisted  upon  because  much,  of  the  knowledge 
of  the  gaseous  exchange  between  the  blood  and  the  air  in  the  hums,  as 
well  as  the  control  of  respiration,  has  been  built  upon  data  obtained  by 
the  Haldane-Priestly  method,  and  in  considering  this  work,  which  we 
shall  do  in  subsequent  pages,  it  is  advisable  that  we  be  aware  of  the 
limitations  of  the  method  employed.  The  method  has  been  an  invaluable 
one  for  opening  up  a  hitherto  entirely  unexplored  field  of  research,  but 
now,  the  pioneer  work  having  been  done,  we  must  employ  methods 
which  will  enable  us  to  explore  more  exactly. 

An  Accurate  Standard  Method  for  Normal  Subjects. — The  most  accu- 
rate method,  and  one  free  from  many  of  the  theoretic  errors  present  in 
the  others,  depends  on  the  relationship  found  to  exist  between  the  dilut- 
ing effect  of  the  air  in  the  dead  space  (see  page  302)  and  the  known  per- 
centage composition  of  the  alveolar  air  in  expirations  which  arc  of  vary- 
ing depths  but  of  equal  <m<l  norma!  duration  and  which  follow  normal 
inspirations  (R.  (i.  Pearce). 

In  this  method  the  subject  is  made  to  breathe  through  valves,  which  automatically 
separate  the  inspired  from  the  expired  air.  The  expired  air  is  led  into  a  tube  con- 
aected  with  two  spirometers  by  two  three-way  stopcocks.     The  spirometers  are  of  the 


346 


THE   RESPIRATION 


Gad-Krogh  type,  one  being  capable  of  holding  ten  liters,  and  the  other  one  and  a  half. 
The  exact  time  during  which  air  enters  is  recorded  by  the  small  spirometer  by  means  of 
a  grooved  dial  on  the  axis  of  the  lid,  on  which  a  thread  works  over  a  system  of  pulleys, 
and  any  movement  is  accurately  recorded  by  a  writing  point  on  the  smoked  paper  of  a 
drum.  The  spirometers  are  connected  so  that  the  air  current  may  be  directed  in  the 
three  following  ways:  (1)  through  Cocks  1  and  2  outside;  (2)  directly  through  both 
cocks  into  the  large  spirometer  for  the  purpose  of  collecting  a  series  of  expirations; 
and  (3)  through  Cock  1  directly  into  the  small  spirometer  for  catching  a  single  expira- 
tion. In  all  experiments  the  first  tilling  of  the  spirometer  is  rejected,  so  that  the  dead 
space  of  the  spirometers  is  filled  with  air  of  approximately  the  same  composition  as  in 
the  succeeding  expirations.  The  time  is  marked  in  seconds  by  a  time  dock.  The  respira- 
tory movements  are  recorded  by  a  pneumograph.     (Fig.  128.) 

The  subject  is  brought  into  respiratory  equilibrium  by  having  him  breathe  through 
the  valves  for  a  period  of  time  before  the  observation.  The  respiratory  movements 
during  this  time  are  recorded  while  the  cocks  are  in  Position  1.  When  the  observation 
is  started,  the  cocks  are  turned  into  Position  2  during  the  time  an  inspiration  is  being 


Fig.    128. — Arrangement   of   meters   and   connections    of   Pearce's   method    for   measurement   of   C02 

of  alveolar   air   in   normal   subjects. 

made,  so  that  the  expirations  which  follow  may  be  collected  in  the  large  spirometer. 
After  about  ten  respirations  (a  counted  number)  have  been  collected,  the  cocks  are 
turned  to  Position  3  during  an  inspiration,  and  a  single  deep  expiration  is  collected 
in  the  small  spirometer.  In  order  that  the  time  of  this  may  be  the  same  as  the  normal 
expiration,  it  is  necessary  to  quicken  it.  This  is  more  or  less  a  chance  procedure,  but 
with  a  little  training,  the  operator  can  close  the  stopcock  with  sufficient  accuracy  to 
interrupt  the  deep  expiration  at  the  end  of  the  normal  expiratory  time.  Should 
there  be  any  gross  variation  from  the  normal  expiratory  time,  the  sample  must  be  col- 
lected again.  Not  infrequently  the  inspiration  immediately  preceding  the  expiration 
into  the  small  spirometer  is  varied  involuntarily  by  the  subject  on  account  of  his  being 
aware  that  the  following  expiration  has  to  be  deepened  and  quickened ;  this  can  be 
partially  overcome  by  giving  him  the  signal  to  breathe  out  deeply  after  he  has  actually 
begun  to  expire. 

Determinations  are  made  of  the  average  volume  of  the  tidal  air  (c.c.  air  in  large 
spirometer  divided  by  number  of  breaths),  of  the  volume  collected  from  the  deep  ex- 
piration, and  of  the  percentage  composition  of  the  tidal  air  and  that  of  the  deep 
expiration.    A  criterion  for  determining  whether  or  not  the  procedure  has  been  carried 


THE    CONTROL   OF    THE   RESPIRATION  347 

oul  c  irrectly  is  the  respiratory  quotient  (ratio  of  C02  excreted  to  02  absorbed).  For 
reasons  which  are  set  forth  above,  the  quotients  should  be  approximately  equal  in  the 
air  collected  in  the  large  and  in  the  small  spirometers]  if  they  are  not  so,  the  condi- 
tions of  the  method  have  not  been  correctly  carried  out. 

Since  the  (had  space  and  the  average  composition  of  the  alveolar  air  under  these 
conditions  may  be  considered  constant,  the  percentage  composition  of  the  deep  expira- 
tion will  differ  from  that  of  the  mixed  sample  of  several  normal  expirations  in  propor- 
tion as  the  dead  space  exerts  a  greater  diluting  effect  in  the  small  than  in  the  large 
ixpiration.  This  being  the  case,  the  data  obtained  can  be  combined  algebraically  to 
give  either  the  capacity  of  the  air  passages  or  the  percentage  composition  of  the 
alveolar  air. 

Let  A  —  amount  of  air  in  large  expiration   (small  spirometer), 
Ai  =  amount  of  air  in  small  or  normal  expiration  (tidal  air), 

B  =  the  percentage  of  CO,  or  02  in  the  expired  air  of  large  expiration, 

Bi  =  the  percentage  of  C02  or  0:  in  the  expired  air  of  small  expiration, 

x  r=  the  capacity  of  the  dead  space, 

y  =  the  average  percentage  of  CO,  or  02  in  the  alveolar  air;  then, 

AxB=  (A  -  x)y  and  Ai  X  Bi  =  (Ai  -  x)y. 

Solving  this  for  x,  y  remaining  constant  under  the  same  physiologic  conditions,  we 

.  AxAix(B-Bi)  .  . 

have :     x  —   ,  the  dead  space.     Or  solving  lor  v,  we  have : 

A  x  B  -  Ai  x  Bi 

,,  the  mean  percentage  of  CO.,  in  the  alveolar  air.     In  case  the 


A-Ai 
dead  space  for  02  is  desired,  B  and  Bi  must  be  made  to  equal  the  02  absorbed. 

Clinical  Method. — The  use  of  the  kymograph  and  pneumograph,  and 
other  complicating  factors,  make  the  method  as  just  described  quite  im- 
practicable for  clinical  procedure,  but  the  use  of  the  same  apparatus 
with  the  following  modification  will  yield  satisfactory  results  for  most 
clinical  purposes.  The  patient  is  made  to  respire  through  the  valves  for 
a  short  time,  after  which  the  observer  collects  a  single  expiration  in  a 
small  spirometer  by  turning  the  stopcock  from  Position  1  to  2.  A  sam- 
.ple  of  this  is  taken  for  analysis,  and  the  spirometer  is  again  emptied 
and  a  series  of  successive  samples  of  deeper  expirations  taken.  This  is 
done  by  directing  the  patient,  after  he  has  started  to  breathe  normally 
into  the  spirometer,  to  breathe  more  deeply.  The  amount  of  air  col- 
lected in  each  expiration  is  controlled  by  the  observer  by  closing  the 
stopcock  when  the  desired  volume  is  obtained.  By  this  means  one  can 
collect  several  expirations  differing  from  one  another  by  increasing 
amounts  but  all  occupying  the  same  time.  The  samples  of  the  various 
expirations  are  collected  in  a  series  of  numbered  sampling  syringes,  and 
the  gaseous  composition  of  each  is  determined.  When  the  percentage 
of  C02  or  02  in  each  expiration  is  plotted  on  cross  section  paper  on  the 
ordinates,  with  the  volume  of  the  expirations  in  c.c.  on  the  abscissae,  a 
hyperbolic  curve  should  be  obtained.  Any  marked  deviation  from  such  a 
curve  indicates  that  some  error  has  been  made  in  taking  a  sample,  and 


:J4s 


Till:    KKSI'IRATION 


this  observation  should  be  discarded.  The  different  observations  are 
then  combined  in  the  formula  given  on  page  -'U7.  The  determination 
of  the  CO,  percentage  of  expired  air  is  so  simple  that  a  number  of  speci- 
mens of  varying  depths  of  expiration  can  be  taken  and  thus  many  points 
on  the  curve  determined.  For  the  most  accurate  results  it  is  in  general 
best  to  compare  only  those  expirations  which  differ  from  one  another 
by  at  least  0.3  per  cent  in  C02  and  by  at  least  200  c.c.  in  volume.  This 
depends  on  the  fact  that  the  diluting  effect  of  the  dead  space  in  reduc- 
ing the  percentage  of  C02  in  the  expired  air  from  that  in  the  alveolar 
air  is  greater  in  relatively  small  expirations.  If  more  exact  work  is  de- 
sired, the  02  content  can  be  determined  on  each  specimen,  the  respiratory 
quotient  calculated,  and  only  those  expirations  which  show  the  same 
respiratory  quotient  combined. 

In  the  table  each  observation  is  compared  with  each  of  the  others  in 
all  possible  combinations. 


TOTAL 

EXPIRED 

AIR 

PER  CENT 
CO,  IN* 
EXPIRED 

AIR 

ALVEOLAR  CO.. 

DEAD  SPACE 

XO.  OF 
OBSERVA- 
TION 

1 

2 

3 

1 

o 

•  > 

1 

2 

O 

4 
5 
6 

450 
637 

750 
960 

1 1 20 

1440 

3.10 
3.66 

4.00 
4.28 
4.30 
4.40 

4.99 
5.34 
5.30 
5.11 

5.16 

5.48 

5.15 
4.98 

5,27 
4.92 

4.82 

170 
189 
189 
1(51 
171 

183 

14n 
127 

214 
184 
171 

General  average  f'n-  CO2  in  alveolar  air,  5.1.'!. 

General  average  for  dead  space,  172.     Dead  space  in  valves  in  this  experiment  was 
about  30  c.c. 


Another  method  which  has  been  su<> jested  for  clinical  purposes  is 
that  of  Plesch;  this  consists  in  having  the  subject  breathe  several  times 
in  and  out  of  a  small  bay.  It  is  assumed  that  after  such  respiration 
the  composition  of  the  air  in  the  bag  will  become  the  same  as  that  in  the 
alveoli.  Although  this  is  no  doubt  true,  it  has  been  shown  that  the 
method  is  fallacious,  because  the  CO,  tension  determined  in  this  way 
is  not  that  of  the  arterial  blood  alone,  but  is  the  average  between  it  and 
that  of  the  venous  blood. 


CHAPTER  XL 
THE  CONTROL  OF  RESPIRATION  (Cont'd) 

THE  NATURE  OF  THE  RESPIRATORY  HORMONE 

The  practical  importance  of  the  observations  described  in  the  foregoing 
chapters   in    the   investigation   of  the   relationship   between   CH   of   the 

blood  and  respiratory  activity  Avill  now  be  plain,  and  it  remains  for  us 
to  consider  the  physiologic  evidence  that  such  a  relationship  exists.  In 
the  first  place,  let  us  consider  the  behavior  of  the  acid-base  equilibrium 
during-  conditions  of  abnormal  breathing' — hyperpnea  and  dyspnea." 

As  CO.,  accumulates  and  0.,  becomes  used  up  in  a  confined  space,  the 
breathing  becomes  intensified.  In  searching  for  the  exact  cause  of  this 
effect,  Ave  must  first  of  all  ascertain  whether  the  hyperpnea  is  due  to  the 
deficiency  of  02  or  to  the  accumulation  of  CO.,.  Many  of  the  experi- 
ments hearing  on  these  problems  can  he  more  satisfactorily  performed  on 
man  than  on  laboratory  animals,  because  anesthesia  is  not  necessary  and 
the  subjective  symptoms  experienced  are  of  great  value  in  the  inter- 
pretation of  the  results.  If  an  individual  is  placed  in  a  large  air-tight 
chamber  (2000  liters'  capacity),  and  the  depth  and  rate  of  breathing  ob- 
served as  the  C02  accumulates  and  the  02  becomes  used  up  in  the  air  of 
the  chamber,  no  distinct  change  in  respiration  will  be  observed  until  the 
CO,  percentage  of  the  air  has  risen  to  almost  3.  Above  this  point,  how- 
ever, the  hyperpnea  becomes  more  and  more  pronounced,  until  finally, 
when  the  C02  percentage  has  risen  to  about  6  and  the  0,  percentage  has 
fallen  to  13.5.  it  becomes  unbearable  (dyspnea).  From  the  results  of  the 
foregoing  observation  alone  we  could  not,  however,  decide  whether  the 
excitation  of  the  respiratory  center  is  due  to  the  deficiency  of  02  or  to 
the  increase  of  C02.  If  the  experiment  is  repeated  with  the  difference 
that  the  C02  as  it  accumulates  is  absorbed  by  soda  lime,  no  hyperpnea 
will  develop  even  when  the  I  >_,  is  as  low  as  in  the  previous  experiment. 
We  may  conclude,  therefore,  that  in  the  first  experiment  C02  accumulation 
must  have  acted  as  tJir  respiratory  stimulus. 

The  same  conclusion  is  arrived  at  as  a  result  of  ohservations  on  indi- 
viduals caused  to  breathe  in  a  more  confined  space  as  into  a  rubber  bag 
of  about  225  liters'   capacity.     Under  these   conditions  hyperpnea   de- 


*Hyperpnea    means    slightly    increased    breathing;    dyspnea,    labored    breathing,    but    yet    with    suffi- 
cient   ventilation    to    maintain    life;    asphyxia,    the    resul's    of    insufficient    breathing. 

349 


350  THE    RESPIRATION 

velops  more  rapidly  than  in  the  large  cabinet,  and  a  higher  percentage 
(10  per  cent)  of  C02  can  be  tolerated.  That  in  this  case  also  deficiency  of 
02  is  not  responsible  for  the  hyperpnea  can  be  shown  by  repetition  of  the 
experiment  either  with  an  excess  of  0,  in  the  bag  or  with  absorption  of  the 
C02  by  soda  lime.  In  the  former  case  hyperpnea  will  develop  as  usual, 
while  in  the  latter  it  will  not  supervene  until  the  percentage  of  02  has 
fallen  below  10,  when  cyanosis  becomes  marked.  In  fact,  some  people 
become  cyanosed  and  unconscious,  and  collapse  under  these  conditions 
before  there  is  any  respiratory  disturbance.  A  peculiarity  of  the  effect 
of  02  deficiency  is  that  the  person  may  be  unaware  of  the  seriousness 
of  his  condition ;  indeed  he  may  be  somewhat  stimulated.  The  conclusion 
may  be  drawn  that  deficiency  of  02  per  se  can  serve  as  a  respiratory 
stimulus  only  when  it  is  so  extreme  as  to  cause  other  serious  symptoms. 
This  conclusion  does  not  rule  out  an  important  influence  of  02  deficiency 
in  increasing  the  excitability  of  the  center  towards  C02.  Under  ordi- 
nary conditions,  however,  the  center  is  far  more  sensitive  towards  slight 
changes  in  the  C02  percentage. 

There  is  an  obvious  reason  why  the  adjustment  of  pulmonic  ventila- 
tion should  not  depend  upon  changes  in  02  supply  to  the  respiratory  cen- 
ter. If  it  were  so,  many  other  tissue  activities  and  other  nerve  centers 
would  suffer  from  the  02  deficiency  before  there  was  time  for  the  breath- 
ing to  become  stimulated  sufficiently  to  make  good  the  loss  of  02.  As  a 
matter  of  fact,  headache,  dizziness,  nausea  and  even  fainting  are  almost 
certain  to  be  caused  whenever  any  muscular  exercise  is  attempted  in  an 
atmosphere  containing  a  deficiency  of  0,  but  no  excess  of  C02  (cf.  moun- 
tain sickness).  An  adequate  02  supply  of  the  body  is,  therefore,  insured 
by  changes  in  CO,  tension  of  the  blood. 

Quantitative  Relationship  between  C02  of  Inspired  Air  and  Pulmonary 
Ventilation. — These  results  suggest,  as  the  next  step  in  the  investigation 
of  our  problem,  the  determination  of  the  quantitative  relationship  be- 
tween the  C02  percentage  of  the  respired  air  and  the  amount  of  air 
breathed  (pulmonic  ventilation).*  That  there  is  such  a  relationship  has 
been  most  successfully  demonstrated  by  R.  W.  Scott,  who  used  for  his 
purpose  decerebrate  cats.f  The  trachea  was  connected,  through  a  T-tube 
provided  with  valves,  with  tubing  leading  to  a  large  bottle  and  a  Gad-Krogh 
spirometer,  so  that  the  animal  breathed  out  of  the  bottle  into  the 
spirometer,    these    two    being    also    connected    together.      The    spirom- 


*A  distinction  is  somewhere  drawn  between  pulmonic  ventilation  ■  and  alveolar  ventilation,  the 
former  being  the  total  amount  of  air  that  enters  and  leaves  the  lungs,  and  the  latter,  that  which  en- 
ters and  leaves  the  alveoli.  This  distinction  is  based  on  the  assumption  that  the  capacity  of  the  dead 
space  may  vary  considerably  from  time  to  time,  which,  as  pointed  out  elsewhere,  is  erroneous.  For 
practical   purposes   pulmonic   ventilation   is   the   safer  value   to  give. 

fDecerebrate  animals  must  be  used  in  these  experiments,  since  anesthetics  markedly  depress  the 
activity  of  the   respiratory  center. 


Till:    CONTROL    ol-'    Till:    RESPIRATION 


351 


eter  was  made  lo  record  its  movements  on  a  drum,  so  that  an  accurate 
record  of  the  depth  and  frequency  of  the  respirations  was  secured.  Sam- 
ples of  air  were  removed  from  the  bottle  by  ground-glass  plunger  syringes 
at  trequenl  intervals  during  the  time  that  the  animal  was  respiring  into 
the  tubing. 


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Fig.  129. — Composite  curve  obtained  from  the  data  on  sixteen  experiments,  showing  the  re- 
spiratory response  to  C02  in  the  decerebrate  cat.  Abscissae  =  percentage  of  CO2  in  the  inspired 
air.     Ordinates  =  the  percentile  increase  the  tidal   air  per  minute.      (From   R.   W.    Scott.) 


The  results  are  given  in  the  accompanying  curve  (Fig.  129),  which  shows 
that  there  is  a  perfect  correspondence  between  the  C02  percentage  in  the 
air  of  the  bottle  and  the  pulmonary  ventilation.  Moreover,  when  the 
bottle  was  filled  with  02  instead  of  air  to  start  with,  the  same  results 
were  obtained,  showing  that  the  C02  accumulation  alone  was  responsible 
for  the  hyperpnea.    In  these  cases  the  percentage  of  02  remaining  in  the 


352  THE    RESPIRATION 

system  after  hyperpnea  had  become  extreme,  was  far  above  thai  a1  which 

direct  excitation  of  the  router  from  02  deficiency  is  possible. 

Experiments  of  a  similar  type  had  previously  been  performed  by  Por- 
ter and  his  pupils.21  but  their  object  was  not  so  much  to  show  the  close 
parallelism  betAveen  the  C02  content  of  the  respired  air  and  the  pulmonic 
ventilation  as  to  demonstrate  the  changes  produced  in  the  sensitivity  of 
the  respiratory  center  in  pneumonia. 

Possibility  that  CO.  Specifically  Stimulates  Center.— After  showing 
that  CO,  acts  as  an  excitant  of  the  respiratory  center,  the  question  arises 
whether  we  are  justified  in  the  assumption  that  has  been  made  tentatively 
that  the  action  depends  on  the  raising  of  the  C„  of  the  blood,  or  whether 
it  may  be  a  specific  action  of  the  HC03  anion  itself.  Many  attempts  have 
been  made  to  decide  this  question  experimentally,  the  general  principle 
of  the  experiments  being  to  determine  whether  CH  of  the  blood  runs 
parallel  with  the  C02  content  of  the  respired  air  and  with  the  hyperpnea. 
Using  the  gas-chaiu  method  (page  31),  Hasselbalch  and  Lundsgaard22 
found  that  the  hyperpnea  produced  in  rabbits  by  breathing  in  C02-rich 
air  runs  approximately  parallel  with  the  increase  in  the  CH  of  the  blood, 
but  on  account  of  the  experimental  difficulties  encountered  they  could  not 
decide  whether  changes  in  CH  are  alone  responsible  for  the  effect,  These 
authors  had  previously  demonstrated  that  changes  in  CH  can  be  induced 
in  blood  removed  from  the  body  by  alterations  in  the  C02  tension  within 
the  physiologic  limits.  An  increase  of  one  millimeter  in  C02  tension 
Avas  found  to  cause  an  increase  in  CH  of  0.0065  x  10  7  (see  page  27). 

R.  W.  Scott's  experiments,  above  referred  to,  have,  however,  yielded 
more  definite  results.  By  using  the  colorimetric  method  for  determining 
CH  of  the  blood  (see  page  32),  it  could  be  readily  shown,  as  is  evident 
from  the  table  (col.  8  in  table),  that  a  marked  rise  in  CH  became  evident 
when  the  inspired  air  contained  5  per  cent  or  more  of  C02.  That  this 
rise  was  due  to  increase  in  the  CO,  tension  was  shown  not  only  by  finding 
a  greater  percentage  of  C02  (col.  15)  in  the  blood,  but  also  by  being  able 
to  demonstrate  that  when  C02-free  air  was  bubbled  through  the  blood 
removed  during  the  dyspnea,  CH  immediately  returned  to  the  normal, 
which  it  also  did  when  the  blood  removed  after  the  animal  had  breathed 
for  a  few  minutes  in  outside  air  (col.  16).  The  C02  content  likewise  re- 
turned (col.  17).  Had  the  increase  in  acidity  been  caused  by  nonvolatile 
acids — lactic,  for  example  — these  results,  particularly  the  latter,  could 
not  have  been  obtained. 

Although  there  is  therefore  no  doubt  that  the  CH  of  the  blood  ma  ' 
be  raised  because  of  an  increase  in  C02  in  solution  in  the  blood  plasma — 
a  C02  acidosis,  as  we  may  call  it  (see  page  351) — this  does  not  prove  that 
the  stimulation  of  the  respiratory  center  is  brought  about  solely  by  CH. 


THE   CONTROL   <>K   THE    RESPIRATION  ■>>>■> 

Tlio  increase  in  the  carbonate  ion  ECOa  LOll  itself  might  also  serve  as 
a  stimulus.  That  sneh  is  actually  Hie  ease  was  demonstrated  by 
finding  that,  if  the  CH  of  the  blood  was  first  of  all  lowered  by  injecting 
alkali  intravenously,  hyperpnea  still  developed  in  proportion  as  the  CO, 
accumulated  in  the  inspired  air;  and  that  CH  of  the  blood,  when  the 
hyperpnea  was  at  its  highest,  was  below  that  of  normal  blood.  Some 
other  factor  than  Cu  nuist  obviously  be  responsible  for  this  result.  This 
must  be  the  HC03  anion. 

The  Effect  of  Re-breathing  Carbon  Dioxide  on  the  Minute  Volume  and  on  the 

H-ion  Concentration  and  Total  Carbonate  Content  of  the  Arterial 

Blood  in  the  Decerebrate  Cat 


FIFTEEN 

MINUTES 

PRELIMINARY  PERIOD 

REBREATHING  PERIOD 

AFTER  RE- 

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7.45 

30.3 

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6.45 

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38.8;  22 

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7.40 

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5.02 

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38.6  28 

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5.35 

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768 

7.45 

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4,536  489 

6.40 

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38.8  32 

896 

7.40 

32.0 

60 

4,800,436 

5.95 

7.20 

50.0 

7.4 

35.2 

Average    - 

32.4 

785 

7.42 

34.1 

*Pn  is  the  actual  value  given  in  the  table.     This  is  inversely  proportional  to  Or. 


Further  corroboration  of  the  claim  that  the  HC03  anion  has  a  specific 
stimulating  effect  on  the  respiratory  center  that  is  independent  of  CH, 
has  been  furnished  by  Hooker,  Wilson  and  Connett."23  These  authors 
succeeded  in  keeping  the  centers  of  the  medulla  alive  by  perfusion  with 
deflbrinated  blood  through  the  blood  vessels  of  the  brain,  and  found 
that,  although  the  respiratory  movements  of  the  diaphragm  became  de- 
pressed with  a  decrease  and  excited  with  an  increase  in  CH  of  the  per- 
fused fluid,  a  greater  activity  of  the  center  was  produced  when  this  con- 
tained a  high  tension  of  C02  than  with  another  fluid  of  the  same  CH 
but  with  a  low  tension  of  C02.  We  conclude  that,  although  the  CH  is  the 
important  respiratory  hormone,  the  carbonate  ion  (HCOz  anion)  also  has 
a  stimulating  influence. 


354  THE   RESPIRATION 

Relationship  Among'  Acidosis  Conditions,  Alveolar  CO.  and  Respir- 
atory Activity. — It  will  be  plain  that  variations  in  the  respiratory  hor- 
mone, whatever  this  may  be,  are  associated  "with  changes  in  the  CO, 
content  of  the  alveolar  air.  Closer  examination  has  shown,  however, 
that  this  relationship  is  by  no  means  always  so  simple  as  in  the  instances 
just  described,  where  increased  respiration  was  found  to  be  associated 
with  an  increase  in  alveolar  CO,.  There  are  many  eases  where  the  re- 
verse relationship  obtains — namely,  decreased  alveolar  C02  and  hy- 
perpnea.  The  whole  question  is  very  closely  linked  with  that  of  the  con- 
trol of  the  reaction  of  the  body  fluids  and  with  the  etiologic  factors  in 
acidosis.  When  it  is  fully  answered,  many  obscure  clinical  conditions  in 
which  respiratory  disturbances  occur  will  be  much  better  understood  than 
they  are  at  present.  On  account  of  its  great  importance,  considerable 
attention  will  be  devoted  in  the  next  few  pages  to  some  of  the  researches 
which  have  been  made  bearing  on  the  relationship  between  the  C02  of 
the  alveolar  air  and  the  various  modified  types  of  breathing  that  can  bo 
produced  experimentally  or  become  developed  under  altered  physiologic 
conditions. 

We  shall  consider  these  conditions  in  the  following  order:  (1)  Con- 
stancy of  the  alveolar  CO,  under  normal  conditions  and  during  moderate 
variations  in  barometric  pressure.  (2)  The  quantitative  relationship 
between  an  artificially  induced  increase  in  alveolar  CO,  tension  (as  by 
breathing  CO,-rich  air)  and  the  increased  respiration.  (3)  The  results 
of  these  observations  will  demonstrate  a  very  precise  relationship  to  exist 
between  alveolar  CO,  tension  and  respiration,  but  if  Ave  proceed  to  repeat 
the  latter  observations  under  conditions  where  the  accumulation  of  C02 
in  the  inspired  air  is  accompanied  by  oxygen  deficiency  (as  by  breathing 
in  a  confined  space),  we  shall  see  that  the  relationship  no  longer  holds, 
indicating  that  the  oxygen  deficiency  has  caused  something  to  happen 
which  disturbs  it. 

We  shall  find  that  the  disturbing  factor  is  accumulation  of  unoxidized 
acids  in  the  blood,  and  this  will  naturally  lead  us  to  study  the  conditions 
in  which  such  acids  might  develop;  namely,  (4)  Breathing  in  rarefied 
air  (mountain  sickness).     (5)  Apnea.     (6)  Muscular  exercise. 

In  succeeding  chapters,  we  intend  to  review  the  work  in  these  fields  in 
considerable  detail,  partly  because  of  its  very  important  bearing  on  the 
general  question  of  the  control  of  the  respiratory  center  and  partly  be- 
cause  of  the  light  the  observations  throw  on  the  nature  of  the  mechanism 
involved  in  the  adjustment  of  the  CH  of  the  blood  and  tissues. 

As  we  have  seen,  much  work  concerning  the  physicoehemical  principles 
involved  in  the  control  of  the  reaction  of  the  blood  has  been  contributed 
during  recent  years  by  physical  and  biological  chemists,  but  much  of  this 


THE   CONTROL   OF   THE    RESPIRATION  355 

work  in  our  judgment  fails  to  pay  sufficienl  regard  to  the  extraordinarilj' 

complicated  conditions  existing  in  the  animal  hotly,  and  more  particu- 
larly, to  correlate  the  purely  physicochemical  data  with  the  numerous 
observations  that  have  from  time  to  time  been  recorded  hy  physiologists 
regarding  the  behavior  of  the  respiratory  center.  Physical  chemists  have 
recently,  for  example,  gone  so  far  as  to  define  acidosis  as  a  conditio!]  in 
which  there  is  a  diminution  in  the  bicarbonate  content  of  the  hlood  in- 
duced by  the  discharge  into  it  of  fixed  acids.  This  is  going  too  far,  for 
it  fails  to  recognize  acidosis  due  to  an  increase  in  the  C02  of  the  blood. 

It  is  the  molecular  ratio    XT  tr^A        which  determines  the  tension  of  C09. 

[_NaHC03  J 

When  C02  is  added  to  the  blood,  either  experimentally  by  respiring  the 
gas,  or  naturally  owing  to  muscular  exercise  or  to  pathologic  conditions  in 
which  there  is  a  deficient  excretion  of  C02,  as  in  heart  disease,  the  ten- 
dency of  the  equation  to  change,  by  increase  of  the  numerator,  is  pre- 
vented partly  by  stimulation  of  the  respiratory  center,  which  gets  rid  of 
C02,  and  partly  by  an  increase  in  the  denominator.  The  respiratory 
center  is  so  sensitive  to  slight  increases  in  CH  that  it  becomes  excited 
before  a  sufficient  increase  in  H2C03  has  occurred  to  disturb  the  normal 

r    TT  PO      ~\ 

ratio     ,.  t-t^A        •     When  fixed  acids  are  added  to  the  blood  the  denom- 
L  NaHC03.  J 

inator  of  the  equation,  NaHC03,  is  lowered  and  consequently  CH  rises, 

and  increased  respiration  occurs,  lowering  H,C03  and  thus  reestablishing 

the  ratio. 


CHAPTER  XLI 

THE  CONTROL  OF  RESPIRATION  (Cont'd) 

THE  CONSTANCY  OF  THE  ALVEOLAR  C02  TENSION 
UNDER  NORMAL  CONDITIONS 

Since  a  close  relationship  exists  between  the  alveolar  CO,  tension  and 
the  respiratory  activity,  it  is  to  be  expected  that  the  two  would  bear  a 
strict  proportionality  to  each  other,  and  since  the  breathing  under  normal 
conditions  does  not  vary  much,  the  C02  tension  should  also  be  constant. 
Many  observations  show  this  to  be  the  case.  The  tension  is  remarkably 
constant  from  day  to  day  and  even  from  month  to  month  in  the  same 
individual,  provided  the  physiologic  conditions  are  the  same.  A  slight 
seasonal  variation  is  said  to  exist,  a  rise  in  the  temperature  of  the  en- 
vironment of  the  individual  causing  a  slight  depression  in  the  C02  ten- 
sion, while  a  fall  in  temperature  causes  a  slight  rise  (Haldane).  These 
changes  are  independent  of  any  demonstrable  change  in  rectal  temper- 
ature and,  therefore,  are  probably  due  to  the  influence  of  the  temperature 
on  the  shin. 

Since  it  is  the  number  of  molecules  of  C02  in  a  given  volume  of  alve- 
olar air  (i.  e.,  the  partial  pressure  or  tension)  that  is  of  importance,  it 
is  only  when  the  barometric  pressure  is  the  same  that  the  percentage  of 
CO,  in  the  sample  of  alveolar  air  can  be  constant.  To  allow  for  this, 
all  results  are  reduced  to  standard  barometric  pressure  (760  mm.  Hg). 
If  the  barometric  pressure  is  lowered,  there  will  have  to  be  a  higher 
percentage  of  C02  in  the  sample  in  order  that  there  may  be  the  same 
tension  of  this  gas  in  the  air  of  the  alveoli ;  and  vice  versa  when  the  bar- 
ometric pressure  is  raised.  The  equation  by  which  this  tension,  ex- 
pressed in  millimeters  of  mercury,  is  determined  is:  100:760::a:p,  where 
a  is  the  percentage  actually  found  in  the  air  of  the  sampling  tube  and  p 
the  tension.  A  correction  must  also  be  introduced  in  this  equation  to 
allow  for  the  vapor  tension  of  the  air  in  the  alveoli,  for  of  course  H20 
molecules  will  behave  like  C02  molecules  in  causing  a  partial  pressure. 

When  reduced  to  this  standard,  it  has  been  found  that  the  tension  of 
C02  in  the  alveolar  air  remains  constant  under  the  different  barometric 
conditions  that  obtain  at  the  top  of  a  mountain  or  at  the  foot  of  a  deep 
mine.     This  is  shown  in  the  following  table: 

356 


THE   CONTROL   OF   THE   RESPIRATION  35*3 


(1)  (2)  (3) 

BAROMETRIC  CO.  ACTUALLY  FOUND  PARTIAL  PRESSURE 

PRESSURE)  IN.  DRY  ALVEOLAR  OF  CO,  IN  MOIST 

(MM.  HO)  AIR  ALVEOLAR  AIR  AFTER 

(  PER  CENT)  CALCULATING  FOR 

BAROMETRIC  PRESSURE 


Top  of  Ben  Nevis 

646.5 

6.62 

5.2.",* 

Oxford 

755 

5.95 

5.5.1 

Foot  of  Dolcoath  Mine 

s .", ' ' 

5.29 

5.48 

<  lompresscd  air  cabinet 

1260 

3.52 

5.64 

B'  "  A  x  P' 
*The  figures  in  this  column  arc  arrived  at  by  the  formula:  jr- =  P>  when  P  =  figures  in 

last  column;  B'  =:  figures  in  first  column;  A  =  aqueous  tension  of  alveolar  air;  P'  =  figures  of 
second  column;  B  =  barometric  pressure  at  sea  level.  A  is  obtained  from  tables  giving  the  aqueous 
tension  at  different  temperatures. 

Changes  in  the  frequency  of  breathing  that  are  within  physiologic 
limits  have  no  influence  on  the  tension  of  alveolar  C02,  provided  that 
exactly  the  same  time  is  taken  in  performing  the  forced  expirations 
during  which  the  samples  of  alveolar  air  for  analysis  are  removed. 

The  DegTee  of  Sensitivity  of  the  Respiratory  Center  to  Changes  in  the 
C02  Tension  of  the  Alveolar  Air 

This  can  be  determined  by  observing  the  alterations  produced  in  the 
volume  of  air  that  actually  enters  the  alveoli  (alveolar  ventilation)  dur- 
ing breathing  in  atmospheres  containing  different  percentages  of  C02. 
In  man  an  increase  of  from  0.2  to  0.3  per  cent  in  the  alveolar  C02  is 
sufficient  to  double  approximately  the  alveolar  ventilation;  or,  more  pre- 
cisely, an  increase  of  ten  liters  in  the  air  entering  and  leaving  the  alve- 
oli per  minute  is  caused  by  raising  the  alveolar  CO,  tension  by  from  2.2 
to  3.1  mm.  Hg  (Douglas,  etc.)24. 

THE  ALVEOLAR  CO,  TENSION  DURING  BREATHING  IN  A 
CONFINED  SPACE 

We  have  already  employed  similar  experiments  in  ascertaining  whether 
C02  accumulation  or  0,  depletion  is  responsible  for  the  hyperpnea  pro- 
duced under  these  conditions.  We  concluded  for  the  former,  but  now 
on  closer  examination  we  shall  see  that,  although  our  conclusion  was 
correct,  the  deficiency  in  02  also  has  an  indirect  effect  on  the  respiratory 
center.  This  is  revealed  by  the  fact  that  the  tension  of  the  C02  in  the 
alveolar  air  does  not  increase  in  proportion  to  the  observed  increase  in 
pulmonary  ventilation.  We  must  conclude  that  the  decrease  in  02  has 
some  effect.  How  may  this  be  explained?  Two  possibilities  exist:  (1) 
that  the  02  want  has  caused  organic  acids  to  accumulate  in  the  blood 
and  so  raise  the  CH ;  and  (2)  that  in  the  absence  of  a  certain  tension  of 


358  THE    RESPIRATION 

02  the  excitability  of  the  center  is  raised  (i.  e.,  its  "threshold"  lowered), 
so  that  it  becomes  stimulated  by  CH,  to  which  ordinarily  it  does  not  re- 
spond. We  shall  now  proceed  to  examine  the  experimental  evidence 
bearing  on  these  possibilities. 

By  examination  of  the  alveolar  air  of  an  individual  confined  in  a  pneu- 
matic cabinet  in  which  the  barometric  pressure  is  gradually  lowered, 
it  has  been  found  that  although  the  C02  tension  remains  constant  for 
a  considerable  range  (cf.  page  35G),  it  begins  to  fall  when  the  barometric 
pressure  has  reached  about  550  mm.  Hg.  At  this  pressure  the  tension 
of  02  in  the  alveolar  air  will  be  62  mm.  instead  of  its  normal  of  about 
105  at  atmospheric  pressure.  Below  it  the  alveolar  C02  tension  quickly 
falls,  and  at  the  same  time  hyperpnea  becomes  evident,  although  the 
person  himself  may  be  unaware  that  he  is  breathing  more  deeply.  If 
this  experiment  is  repeated  with  the  difference  that,  as  the  pressure  is 
lowered,  an  excess  of  02  is  introduced  into  the  chamber,  the  hyperpnea 
does  not  supervene  until  a  barometric  pressure  has  been  reached  that  is 
distinctly  lower  than  when  no  excess  of  02  is  present,  and  at  the  same 
time  the  C02  tension  in  the  alveolar  air  remains  unchanged.  The  ex- 
planation of  this  result  is  that  by  lowering  the  02  tension  in  the  alveolar 
air  and,  therefore,  in  the  blood  and  tissues,  oxidative  processes  become 
depressed  so  that  unoxidized  acids,  such  as  lactic,  accumulate  in  the 
blood  and  by  adding  their  effect  to  that  of  the  C02  serve  to  raise  the  CH 
of  the  blood.  As  a  result,  the  respiratory  center  becomes  excited,  hy- 
perpnea supervenes,  and  the  volatile  C02  is  removed  from  the  blood  into 
the  alveolar  air.  On  supplying  02  artificially,  this  failure  of  proper 
oxidation  does  not  set  in  and  breathing  goes  on  normally. 

There  should  be  a  stage  in  the  above  experiment  during  which  the 
CO,  tension  of  the  alveolar  air  is  increased — namely,  when  the  fixed  acids 
first  appear  and  decompose  the  carbonates  of  the  blood.  This  stage  has, 
however,  not  been  detected.  When  a  person  is  kept  in  such  a  chamber 
for  some  time  at  a  pressure  which  causes  a  diminution  in  the  alveolar 
C02  tension,  the  tension  does  not  immediately  return  to  its  normal  level 
when  atmospheric  air  is  again  breathed,  indicating  that  the  fixed  acids 
are  only  slowly  got  rid  of. 

The  second  hypothesis — namely,  that  the  02  deficiency  directly  raises 
the  excitability  of  the  respiratory  center — has  many  advocates,  among 
them  Lindnard,25  who  found  that,  when  the  percentage  of  02  in  the  alve- 
olar air  was  raised,  a  higher  percentage  of  C02  was  necessary  to  cause 
an  increase  in  the  ventilation  of  the  lungs,  and  conversely,  that  a  distinct 
increase  in  the  excitability  of  the  center  occurred  when  the  inspired  air 
contained  less  than  the  normal  percentage  of  02.  Although  it  is  ad- 
mitted by  Haldane  and  his  school  that  such  alteration  in  the  excitability 


Till:   CONTROL   OP   THE   RESPIRATION  359 

of  the  respiratory  center  to  the  <\i  of  the  Mood  may  occur  after  Long 
continued  exposure  of  the  center  to  the  changed  tension  of  02,  yet  they 
deny  that  such  alteration  can  occur  as  a  temporary  condition.     These 

\vorkcrs  round  that,  in  order  to  raise  the  pulmonic  ventilation  by  100 
pel-  cent,  the  increase  in  the  alveolar  C02  tension  required  was  practically 
the  same  (0.3  per  cent)  when  the  inspired  air  contained  20  per  cent  of 
Oj  as  when  it  contained  54  per  cent. 

In  the  observations  already  referred  to  on  the  decerebrate  cat,  B.  W. 
Scott-"  has  secured  some  evidence  that  would  seem  to  support  Ilaldane's 
contention.  He  found  that  the  response  of  the  respiratory  center  to  the 
percentage  of  C02  in  the  respired  air  was  exactly  the  same  whether  the 
latter  contained  a  low  (18-14)  or  a  high  (30  and  over)  percentage  of  02. 
The  possibility  that  the  excitability  of  the  respiratory  center  is  affected 
directly  by  the  02  tension  is  to  be  considered  as  one  of  the  most  im- 
portant problems  awaiting  solution. 

Even  if  it  may  have  a  certain  influence  on  the  excitability  of  the  re- 
spiratory center,  02  deficiency  per  se  can  serve  as  a  direct  stimulus  of 
the  center  only  Avhen  it  is  of  extreme  degree.  Much  light  has  been 
thrown  on  the  relationship  of  02  to  respiratory  activity  by  observing 
the  respirations  during  breathing  in  and  out  of  rubber  bags  through 
soda  lime  absorption  bottles  of  sufficient  size  to  remove  the  C02.  "We 
have  already  seen  that  even  the  general  results  of  such  observations 
(page  349)  show  clearly  how  much  more  potent,  a  respiratory  stimulant 
is  accumulation  of  C02  than  deficiency  of  02.  More  particular  investi- 
gation in  Avhich  the  alveolar  air  is  analyzed  bears  out  these  conclusions 
and  at  the  same  time  indicates  the  exact  conditions  under  which  organic 
acids  become  developed. 

With  a  very  small  bag  (a  few  liters'  capacity)  hyperpnea  of  a  dis- 
tressing type  but  without  cyanosis  supervenes  in  a  few  minutes,  and  the 
alveolar  air  contains  perhaps  as  low  as  6  per  cent  02  and  4  per  cent  C02. 
<  )f  still  greater  interest  and  significance,  hoAvever,  is  the  fact  that  the 
ratio  betAveen  the  Arolume  of  C02  excreted  and  of  02  absorbed  (respira- 
tory quotient)  during  the  hyperpnea  is  raised  considerably  abo\re  unity, 
indicating  that  an  excessive  excretion  of  C02  must  be  occurring.  This 
result  is  explained  by  assuming  that  the  deprivation  of  02  causes  large 
quantities  of  fixed  acids  to  be  produced,  and  that  these  expel  C02  from 
the  blood  more  quickly  than  the  02  is  absorbed.  In  corroboration  of 
this  explanation,  it  has  been  observed  that,  after  outside  air  is  breathed 
for  some  time  folloAving  the  above  experiment,  the  respiratory  quotient 
becomes  very  low,  so  that  CO,  must  iioav  be  accumulating  in  the  blood. 

If  the  above  experiment  is  repeated  with  a  larger  bag  (about  200 
liters),  so  that  the  O,  falls  slowly,  the  breathing  can  be  maintained  for 


360  THE    RESPIRATION 

a  much  longer  period  without  any  evident  symptoms  of  hyperpnea,  even 
though  the  0,  percentage  in  the  alveolar  air  may  fall  as  low  as  in  the 
previous  experiment,  and  there  are  marked  symptoms  of  02  want,  such 
as  cyanosis,  twitching  of  the  muscles  of  the  hands,  lips,  etc.  The  re- 
spiratory quotient  does  not  become  abnormal  in  this  experiment  indicat- 
ing that  no  expulsion  of  CO,  from  the  blood  can  have  occurred  as  in 
the  previous  experiment.  The  cause  for  the  virtual  absence  of  hyper- 
pnea  in  this  experiment  is  no  doubt  that  the  more  gradual  reduction  in 
02  of  the  alveolar  air  and  therefore  of  the  blood  did  not  bring  about  the 
accumulation  of  lactic  acid  at  a  rate  that  was  greater  than  that  at  which 
the  C02  Avas  got  rid  of  into  the  alveolar  air. 

BREATHING  IN  RAREFIED   AIR;   MOUNTAIN  SICKNESS 

In  considering  the  part  played  by  fixed  organic  acid  in  the  control 
of  the  CH  of  the  blood,  the  most  important  results  have  been  secured 
by  observations  on  the  condition  of  individuals  living  at  high  altitudes. 
As  is  well  known,  under  these  conditions  certain  symptoms  are  likely 
to  develop,  the  condition  being  known  as  mountain  sickness.  The  great 
interest  which  physiologists  have  taken  in  this  subject  has  been  owing, 
not  so  much  to  the  importance  of  the  observations  in  connection  with 
the  condition  itself,  as  to  the  light  which  they  throw  on  the  mechanism 
of  respiratory  control  and  on  the  cause  for  abnormal  types  of  breathing. 

More  or  less  hyperpnea,  especially  on  exertion,  soon  appears  in  a 
rarefied  atmosphere,  and  the  alveolar  C02  tension  assumes  a  value  con- 
siderably below  the  normal.  For  example,  at  sea  level  the  minute  vol- 
ume of  air  breathed  in  one  individual  was  10.4  liters,  and  the  alveolar 
C02  tension  39.6  mm.  Hg.  After  being  some  time  on  Pike's  Peak,  where 
the  barometer  registers  only  459  mm.  Hg,  Douglas26  found  the  minute 
volume  of  air  to  be  14.9  liters,  and  the  alveolar  CO,  tension  27.1  mm.  Hg. 
At  first  sight  the  above  statement  may  seem  to  contradict  one  pre- 
viously made,  to  the  effect  that  the  alveolar  CO,  tension  remains  constant 
at  different  barometric  pressures.  This  applies,  however,  to  the  imme- 
diate effects,  whereas  we  are  now  considering  the  later  effects.  The  im- 
portant point  is:  How  are  we  to  reconcile  with  the  above  hypothesis  the 
fact  that  a  diminution  in  the  alveolar  CO,  tension  should  be  accompanied 
by  hyperpnea?  A  solution  of  the  seeming  contradiction  will  not  only 
be  of  importance  in  connection  with  our  present  problem,  but  will  assist 
us  in  the  investigation  of  the  clinical  conditions  of  hyperpnea,  in  which 
likewise  a  diminished  CO,  alveolar,  tension  is  often  observed.  Mountain 
sickness  may  indeed  he  considered  as  an  intermediate  condition  tetiveen 
the  physiologic  and  the  pathologic. 

From  what  we  have  learned  we  should  expect  the  above  result  to  be 


THE    CONTROL   OF    THE    BESPIRATION 


861 


dependenl  upon  an  increase  in  the  nonvolatile  acid  contenl  of  the  blood 
Thai  such  is  really  the  rase  has  been  conclusively  shown  both  by  titra- 
tion methods  and  by  observing  the  dissociation  curve  of  hemoglobin, 
which,  as  will  be  explained  later  (see  page  386),  may  be  made  to  Berve 


O      O 

Tig.  130.— The  horizontal  interrupted  lines  represent  the  mean  normal  alveolar  CO,  and  O, 
pressures  at  sea  level  (i.e.,  Oxford  and  New  Haven);  the  thick  line,  alveolar  CO,  P"ssu"'  dml 
the    thin   line,    alveolar    Q_.    pressure.      (From    Douglas,    Haldane,    Henderson,    and    SchneideiJ 

as  an  index  of  the  H-ion  concentration  of  the  blood.  The  exact  chemical 
nature  of  the  nonvolatile  acids  that  accumulate  in  the  blood  is  not  as  yet 
known.    Two  types  of  acid  can  be  thought  of,  either  unoxidized  organic 


362  THE    RESPIRATION 

acids,  of  which  lactic  acid  may  be  taken  as  the  representative,  or  inor- 
ganic substances,  like  the  acid  phosphates.  That  it  is  not  lactic  acid  is 
shown  by  both  direct  and  indirect  evidence.  The  direct  evidence  has 
been  furnished  by  Ryffel,  who  was  unable  to  find  any  increased  per- 
centage of  this  substance  either  in  the  urine  or  in  the  blood  of  persons 
who  had  been  living  for  some  time  in  the  famous  Regina  Margherita 
hut  on  Monte  Rosa.27  The  indirect  evidence  has  been  furnished  by  ob- 
serving the  time  that  it  takes  after  the  individual  has  started  breathing 
the  rarefied  air  for  the  alveolar  C02  tension  to  fall,  as  well  as  that  re- 
quired to  bring  about  the  recovery  to  the  normal  when  he  descends  to 
sea  level.  The  following  curve,  which  is  self-explanatory,  will  illustrate 
these  points. 

Thus,  on  Pike's  Peak,  where  the  barometric  pressure  is  459  mm.  Hg, 
the  C02  tension  after  an  initial  fall  took  about  seven  days  before  it 
came  to  its  permanent  level  for  that  barometric  pressure,  and  fourteen 
days  elapsed  after  descending  from  the  mountain  before  the  sea-level 
tension  had  been  regained.  The  slow  nature  of  these  changes,  when  com- 
pared with  the  rapid  changes  observed  in  the  experiment  with  the  bags 
already  alluded  to  (page  358),  shows  clearly  that  lactic  acid  can  not  be 
responsible  for  the  increase  in  H-ion  concentration  in  mountain  sickness. 
By  exclusion  it  would  appeal-  that  the  increase  in  CH  is  the  result  of  an 
excess  of  fixed  inorganic  acid  (H,P04)  in  the  blood  dependent  on  a  dis- 
proportionate excretion  of  bases  by  the  kidneys  during  the  period  of 
acclimatization  to  the  rarefied  air. 

Other  observers  aver  that  the  acidosis  does  not  really  exist,  but  that 
the  excitability  of  the  respiratory  center  itself  becomes  raised  (its 
threshold  lowered),  so  that  it  responds  more  readily  to  the  normal  CH 
of  the  blood.  It  has  been  stated  that  the  increase  in  excitability  of  the 
center  is  dependent  upon  the  action  of  the  intense  light  rays  at  high 
altitudes — the  erythema  of  the  skin,  etc.,  being  evidence  of  this  excit- 
ing action  of  light.  The  constant  irritation  of  the  skin,  these  authors 
say,  serves  by  stimulation  of  afferent  nerves  to  maintain  a  hyperexcit- 
ability  of  the  respiratory  center.  Others  believe  that  the  hyperexcit- 
ability  of  the  center  is  a  direct  result  of  the  maintained  0,  deficiency. 
The  balance  of  evidence,  however,  stands  in  favor  of  the  view  that  the 
phenomena  of  mountain  sickness  depend  on  changes  occurring  in  the  in- 
organic nonvolatile  acids  of  the  blood.  The  other  phenomena  of  this 
interesting  condition  will  be  discussed  elsewhere  (page  399). 

APNEA 

If  a  man  breathes  forcibly  and  quickly  for  about  two  minutes,  he 
will  experience  no  desire  to  breathe  for  a  further  period  of  about  the 


THE   CONTROL   OF   THE   RESPIRATION  363 

same  duration — he  becomes  apneic.  When  flic  desire  to  breathe  re- 
turns, the  breathing  is  at  first  very  shallow,  bu1  gradually  becomes  more 
marked,  until  at  last  normal  respiration  is  reestablished.  If*  a  sample  of 
alveolar  air  is  removed  at  the  time  when  the  desire  to  breathe  returns, 
it  will  be  found  to  contain  a  very  small  percentage  of  02  indicating 
that  for  some  time  previous  to  the  onset  of  breathing  there  had  been  in 
the  alveolar  air,  and  therefore  in  the  blood,  so  low  a  percentage  of  0. 
that  if  Oo  deficiency  could  stimulate  breathing,  this  would  have  started 
much  earlier  than  it  actually  did.  A  curve  showing  the  results  of  such 
an  experiment  by  Haldane  is  given  in  Fig.  131.  The  person  may  begin 
to  show  symptoms  of  Oo  want,  such  as  cyanosis,  before  the  desire  to 
breathe  returns,  which  furnishes  strong  proof  that  02  want  itself  can 
not  serve  as  a  stimulus  to  the  respiratory  center.  The  failure  of  the 
center  to  act  must  rather  be  due  to  the  lowering  of  the  CH  consequent 
upon  the  removal  of  C02  from  the  blood  by  the  forced  respiration  which 
preceded  the  apnea — washing  out  of  the  C02,  as  it  is  called.  That  this 
has  really  occurred  can  readily  be  shown  by  estimating  the  C02  con- 
tent of  a  sample  of  alveolar  air  collected  by  having  the  subject  make  a 
forced  expiration  early  in  apnea.  Extremely  low  values  along  with  a 
respiratory  quotient  (page  547)  of  about  0.2  are  often  found,  whereas, 
during  the  preceding  forced  breathing  while  the  C02  is  being  washed 
out,  the  quotient  is  often  ten  times  as  great — viz.,  2.0. 

As  would  be  expected,  the  low  0,  percentage  present  in  the  alveolar 
air  toward  the  end  of  the  apheic  pause  is  not  without  some  effect,  indi- 
rect though  it  may  be,  on  the  excitability  of  the  respiratory  center. 
This  accounts  for  the  fact  that  the  alveolar  air,  at  the  moment  the  de- 
sire to  breathe  returns,  usually  contains  a  lower  percentage  of  C02  than 
the  normal,  indicating  that  some  nonvolatile  acid  must  have  accumulated 
in  the  organism  so  as  to  raise  the  CH  of  the  blood,  and  thus  require  a 
lower  tension  of  C02  to  overstep  the  threshold  of  excitability  of  the  re- 
spiratory center.  In  agreement  with  this  explanation  it  has  been  found 
that,  if  the  last  two  or  three  forced  respirations  preceding  the  apnea 
are  made  in  an  atmosphere  of  0,  instead  of  air,  so  as  to  fill  the  alveoli 
with  02,  the  apnea  can  be  maintained  for  a  very  much  longer  period ; 
and  when  the  natural  desire  to  breathe  returns,  the  C02  tension  of  the 
alveolar  air,  instead  of  being  below  the  normal,  is  above  it.  The  effect 
of  02  in  prolonging  apnea  must,  therefore,  be  dependent  on  the  fact  that 
it  prevents  the  accumulation  in  the  organism  of  the  unoxidized  acids, 
leaving  to  C02  alone  the  function  of  raising  the  CH  in  the  blood  to  the 
level  required  to  excite  the  respiratory  center.  By  this  means  the  period 
during  which  the  breath  can  be  held  after  breathing  02  is  sometimes 


364 


THE   RESPIRATION 


a  s  j x 


Fig.  131. — Curves  showing  variations  in  alveolar  gas  tensions  after  forced  breathing  for  two 
minutes.  Thin  line  =  02  tension;  thick  line  -■  C02  tension.  Double  line  =  normal  alveolar 
C02  tension.  Dotted  line  shows  the  alveolar  C02  tension  at  which  breathing  would  recommence 
at  the  end  of  apnea  with  the  alveolar  02  pressures  shown  by  the  thin  line.  The  actual  breathing 
is  indicated  at  the  lower  part  of  the  figure.  It  is  periodic  to  start  with.  (From  Douglas  and 
ETaldane.) 


THE   CONTROL   OF   THE    RESPIRATION  365 

phenomenal;  in  one  individual,  for  example,  after  breathing  Eorcibly  for 
a  few  minutes  and  then  filling  the  lungs  with  02,  apnea  lasted  Eor  eighl 
minutes  and  seventeen  seconds. 

The  Supposed  Nervous  Element  in  Apnea 

It  is  necessary  to  point  out  that,  prior  to  the  elaboration  of  accurate 
methods  for  the  investigation  of  the  chemistry  of  respiration,  many 
physiologists  interpreted  the  apnea  following  forced  breathing  as  the 
result  of  a  sort  of  inhibition  of  the  respiratory  center  brought  about  by 
its  repeated  stimulation  by  afferent  nervous  impulses  transmitted  to  it 
along  the  vagus  nerves,  these  impulses  being  set  up  by  the  frequent  col- 
Lapse  and  distention  of  the  alveoli  acting  on  the  terminations  of  the 
nerve.  In  justification  of  the  nervous  interpretation  of  apnea,  it  was 
claimed  by  the  earlier  observers  that  it  could  not  readily  be  produced 
in  animals  after  severing  both  vagus  nerves.  More  recent  work  has 
shown  that  this  is  not  an  accurate  observation,  for  if  the  severing  of 
the  vagi  is  accomplished  not  by  cutting  but  by  freezing,  then  apnea  is 
as  readily  produced  as  in  an  intact  animal  (Milroy).28 

That  chemical  and  not  nervous  factors  cause  the  apnea  is  further 
demonstrated  by  the  well-known  experiment  of  Fredericq,  who,  after 
ligating  the  vertebral  and  one  of  the  carotid  arteries  in  two  dogs,  anas- 
tomosed the  central  end  of  the  remaining  carotid  of  the  one  to  the 
peripheral  end  of  the  carotid  of  the  other  animal,  thus  establishing  a 
crossed  circulation.  He  then  found  that  by  applying  forced  artificial 
respiration  to  the  one  animal,  the  apnea  which  supervened  affected  the 
other  animal  and  not  that  to  which  the  artificial  respiration  had 
actually  been  applied.  Another  proof  of  the  chemical  theory  of 
apnea  is  furnished  by  the  observation  that  if  forced  breathing  is  per- 
formed in  an  atmosphere  containing  CO,  in  about  the  same  partial  pres- 
sure as  in  the  alveolar  air,  no  apnea  supervenes,  and  if  the  experiment 
is  repeated  several  times  with  progressively  declining  percentage  of 
CO,  in  the  air  each  time,  the  length  of  the  apneic  pause  proportionally 
increases  as  the  CO,  pressure  in  the  inspired  air  diminishes. 

Although  in  the  foregoing  account  we  have  adopted  Haldane's  view 
that  oxygen  deficiency  per  se  can  act  as  an  excitant  of  the  respiratory 
center  only  when  it  is  of  extreme  degree,  it  should  nevertheless  be  pointed 
out  that  studies  by  A.  S.  Loevenhart  on  the  action  of  cyanides  on  the 
respiratory  center  have  led  him  to  conclude  that  interference  with  oxida- 
tive processes  may  be  a  more  potent  factor  in  its  stimulation  than  the 
experiments  in  which  oxygen-poor  atmospheres  are  respired  would  lead 
us  to  expect.  We  must  await  further  evidence  before  a  final  verdict  is 
pronounced  on  this  most  perplexing  problem  of  modern  physiology. 


CHAPTER  XLII 

THE  CONTROL  OF  RESPIRATION  (Cont'd) 

THE  EFFECT  OF  MUSCULAR  EXERCISE  ON  THE 
RESPIRATION 

During  muscular  exercise  the  pulmonic  ventilation  increases  to  an 
extraordinary  extent.  At  rest  an  average  man  respires  6  to  8  liters  of 
air  per  minute,  but  during  walking  on  the  level  at  the  rate  of  5  kilometers 
an  hour,  this  figure  may  increase  to  about  20  liters. 

The  first  investigations  as  to  the  cause  of  the  relationship  between 
muscular  activity  and  pulmonic  ventilation  were  made  by  animal  ex- 
periments in  which  tetanus  of  the  muscles  of  the  hind  limbs  was  pro- 
duced by  electric  stimulation  of  the  spinal  cord.  The  problem  was  to 
find  out  what  serves  as  the  means  of  correlation  (nerve  reflex  or  hormone 
control)  between  the  muscular  activity  and  the  respiratory  activity. 
By  cutting  the  spinal  cord  above  the  point  of  stimulation,  it  was  found 
that  the  tetanus  was  still  accompanied  by  as  marked  a  hyperpnea  as 
before.  On  the  other  hand,  when  the  spinal  cord  was  left  intact  but  the 
blood  vessels  of  the  limb  Avere  ligated,  no  hyperpnea  folloAved  the  teta- 
nus.    Evidently  therefore  the  pathway  of  communication  is  the  blood. 

The  next  step  was  to  seek  in  the  blood  for  the  substance  or  hormone  that 
acted  as  the  respiratory  excitant,  and  naturally  the  first  possibility  con- 
sidered was  a  change  in  the  gases  of  the  blood,  either  a  deficiency 
of  02  or  an  increase  in  C02.  Direct  examination  of  the  blood  for  the 
quantity  of  these  gases,  however,  yielded  results  Avhich  Avere  quite  con- 
trary to  such  an  hypothesis.  It  was  found  that  the  percentage  of  0,, 
if  anything,  was  slightly  increased,  and  that  of  the  C02,  if  anything, 
diminished.  Moreover,  when  the  expired  air  was  analyzed  during  the 
hyperpnea,  the  percentage  of  C02  contained  in  it  Avas  distinctly  beloAV 
the  normal  average,  and  the  percentage  of  02  above  it.  Evidently,  there- 
fore, the  amount  of  gases  in  the  blood  has  nothing  to  do  with  the  excita- 
tion of  the  respiratory  center,  and  the  conclusion  drawn  by  the  earlier 
investigators  Avas  to  the  effect  that  the  exciting  substance  carried  from 
the  active  muscles  to  the  respiratory  center  must  be  some  unusual  meta- 
bolic product,  possibly  the  lactic  acid  produced  by  contraction. 

It  Avas  further  found,  by  examination  of  the  respiratory  quotient,  that 

366 


THK    cnXTRnl.    OP    THE    RESPIRATION 


rtr.7 


an  excess  of  C0a  was  being  expired  during  the  work  and  immediately 

alter  it,  but  that  this  was  subsequently  followed  by  a  much  lower  quo- 
tient, indicating  that  C02  was  being  retained.  Such  a  result  would  be 
in  conformity  with  the  view  that  an  acid  such  as  lactic  is  discharged 
into  the  blood,  on  the  carbonates  of  which  it  would  ad  as  explained  on 
page  355.  Breathing  in  and  out  of  a  small  rubber  bag  causes  the  same 
alterations  in  the  respiratory  quotient   (see  page  :J.">8) . 

That  lactic  acid  is  actually  produced  by  contracting  muscle  could  not. 
however,  be  shown  by  all  investigators,  and  it  was  not  until  some  years 
later  that  Fletcher  and  Hopkins20  clearly  demonstrated  the  conditions 
under  which  it  may  appear  in  active  isolated  muscle.  These  observers 
found  that  lactic  acid  is  produced  in  excised  muscles  only  when  the 
muscular  contraction  occurs  in  a  deficiency  of  02.  When  it  occurs  in  an 
adequate  supply  of  0,,  C02  instead  of  lactic  acid  is  produced. 

Taking  these  facts  together  with  what  we  already  know  concerning 
the  conditions  under  which  the  respiratory  center  reacts  to  conditions 
which  presumably  cause  a  change  in  the  CH  of  the  blood,  we  may  formu- 
late the  hypothesis  that  respiratory  activity  during  muscular  exercise 
is  due  to  a  slight  increase  in  the  CH  of  the  blood,  and  that  this  increase 
is  owing  partly  to  an  actual  increase  in  C02  production  by  the  acting 
muscles  and  partly  to  the  production  of  lactic  acid.  Such  an  hypothesis 
would  satisfactorily  explain  why  the  actual  amount  of  C02  in  the  blood 
might  be  below  the  normal  during  muscular  exercise,  for  the  C02  would 
be  "washed  out"  from  the  blood  by  the  hyperpnea  induced  by  the  in- 
crease in  CH. 

The  obvious  method  of  putting  this  hypothesis  to  the  test  is  to  ex- 
amine the  alveolar  C02  tension  and  the  respiratory  quotient  under  various 
conditions  of  muscular  activity.  The  results  of  such  observations  are 
given  in  the  accompanying  table. 


(1) 

(2) 

(3) 

(4) 

(5) 

(X  used 

CO..  pro- 

R.Q. 

CO,  in 

Total  alveolar 

in  c.e. 

duced  in  c.e. 

vol.  C02 

alveolar 

ventilation  in 

per  min. 

per  min. 

vol.  02 

air 

liters  per  min. 

1. 

During  rest,   standing 

328 

204 

0.S04 

5.70 

5.80 

2. 

Walking  at  the  rate  of 

3  kilometers  per  hour 

780 

0(32 

0.840 

0.04 

13.6 

3. 

Walking  at  the  rate  of 

5  kilometers  per  hour 

1005 

922 

0.806 

0.10 

1S.S 

4. 

Walking  at  the  rate  of 

6  kilometers  per  hour 

1.105 

1308 

0.S76 

0.30 

27.6 

5. 

Walking  at  the  rate  of 

7  kilometers  per  hour 

2005 

1788 

0.891 

6.20 

35.6 

6. 

Walking  at  the  rate  of 

S  kilometers  per  hour 

2543 

2386 

0.938 

6.10 

48.2 

368  THE   RESPIRATION 

In  the  first  column  is  given  the  02  used  in  c.c.  per  minute.  Among  other 
tilings  these  figures  indicate  the  actual  amount  of  work  done.  In  the 
second  column  is  given  the  C02  production  in  c.c.  per  minute.  By  divid- 
ing the  figures  of  the  second  column  by  those  of  the  first,  we  obtain  the 
figures  of  the  third  column,  representing  the  respiratory  quotient.  The 
fourth  column  gives  the  C02  content  of  the  alveolar  air,  and  the  last 
column  the  total  alveolar  ventilation  in  liters  per  minute. 

Taking  for  the  present  the  figures  in  the  first  and  fourth  columns  and 
postponing  a  consideration  of  the  respiratory  quotient,  it  will  be  noted 
that,  as  the  muscular  work  increases  up  to  a  total  consumption  of  about 
1600  c.c.  of  0,  per  minute,  the  C02  percentage  in  the  alveolar  air 
steadily  increases.  The  question  arises,  does  the  alveolar  ventilation 
increase  in  proportion  to  the  increase  in  C02  tension?  If  it  does  so, 
increase  in  C02  tension  in  the  blood  can  be  held  solely  responsible  for 
the  hyperpnea  (i.  e.,  a  pure  C02  acidosis);  whereas  if  the  hyperpnea  is 
greater  than  can  be  accounted  for  by  the  increase  in  C02  tension,  other 
acids  must  be  partly  responsible  for  the  acidosis.  By  making  this  same 
individual  breathe  atmospheres  containing  different  percentages  of  CO, 
it  was  found  that  to  produce  a  doubling  of  the  alveolar  ventilation  it 
required  an  increase  amounting  to  0.33  per  cent  of  an  atmosphere  of  C02 
in  the  alveolar  air  (see  also  page  357).  When  we  examine  the  above 
figures  during  muscular  exercise,  however,  we  find  that  a  rise  in  alveolar 
CO,  from  5.70  to  6.36  (i.  e.,  0.66  per  cent)  multiplied  the  normal  alveolar 
ventilation  by  considerably  more  than  four  times,  whereas  had  it  been 
entirely  due  to  an  increase  in  CO,,  it  should  not  have  been  more  than 
twice  as  much.  Evidently  therefore,  some  other  factor  than  CO,  tension 
must  have  been  responsible  for  the  increased  respiratory  activity.  This 
conclusion  is  further  confirmed  by  examination  of  the  alveolar  CO, 
during  very  strenuous  muscular  effort,  when  a  relative  decrease  in  the 
C02  percentage  becomes  apparent. 

If  it  is  true  that  the  exciting  agency  has  been  dependent  partly  on  an 
increase  in  the  C02  tension  of  the  blood,  and  partly  on  the  production  of 
nonvolatile  organic  acids  (lactic  acid),  we  should  expect  that  imme- 
diately after  discontinuing  the  muscular  exercise  the  CO,  tension  of  the 
alveolar  air  would  fall  to  a  level  distinctly  below  normal,  that  it  would 
only  slowly  recover  thereafter,  and  that  further  exercise  before  the  re- 
covery had  occurred  would  produce  only  a  slight  increase  in  alveolar 
CO,.  These  results  we  should  expect  because  of  the  much  slower  rate  at 
which  the  nonvolatile  organic  acid  is  got  rid  of  from  the  organism,  com- 
pared with  the  volatile  CO,.  By  actual  experiment  these  suppositions 
have  been  found  to  be  correct,  as  is  shown  in  the  following  table. 


10 

" 

:;' 

0" 

G' 

30" 

11" 

'  30' 

L0 

" 

V 

0" 

6' 

30" 

10 

n 

3' 

0" 

8' 

30" 

18' 

'  30 

24' 

'  0" 

Till     CONTROL   OF   THE   RESPIRATION  300 


TIM  K  AFTER  DISCONTINUING  ALVEOLAR  C02  TENSION 

A  BRIEF  PERIOD  OF  IX  MM.  EG 

MUSCULAR  EXERCISE 

Period  10"  49.2 

35.4 
35.3 

35.8 

38.9 
33-7 
34.4 

36.9 

34.4 
32.4 
33.7 
36.2 
Normal  resting:  39.0 

(Douglas.) 

Iii  this  table  the  figures  of  Period  1  represent  the  alveolar  C(  >2 
tension  in  mm.  Hg  immediately  following  a  period  of  strenuous  work. 
The  figures  in  Period  2  are  for  the  same  individual  again  performing 
the  same  amount  of  work  with,  however,  only  a  short  period  of  rest  in- 
tervening, and  the  figures  of  the  third  period  are  a  repetition  of  the  same 
conditions.  It  will  be  observed  that  the  muscular  exercise  at  first  raised 
the  alveolar  tension  of  C02  from  the  normal  of  39  mm.  to  49.2  mm.,  but 
that  in  three  minutes  after  the  work  had  been  discontinued  the  tension 
was  considerably  below  the  normal.  During  the  second  period  of  mus- 
cular exercise  the  C02  in  the  alveolar  air  collected  immediately  after  the 
effort  did  not  increase  above  the  normal  level,  and  in  the  third  period 
the  increase  was  still  less — results  which  are  entirely  in  conformity  with  the 
view  that  as  a  consequence  of  the  first  period  of  muscular  exercise  non- 
volatile organic  acids  had  accumulated  in  the  blood,  so  that  to  produce 
the  required  respiratory  activity  in  the  second  and  third  periods  a 
much  less  increase  in  C02  tension  was  required. 

We  may  sum  up  the  conclusions  which  these  observations  justify  by 
stating  that  during  muscular  exercise  the  CH  of  the  blood  becomes  slightly 
increased  because  of  the  liberation  into  it  of  CO,  and  of  lactic  acid  from 
the  acting  muscles.  The  respiratory  center  is,  however,  so  sensitive  to 
the  slightest  increase  in  CH  that  it  immediately  responds  and  produces 
hyperpnea,  with  the  result  that  the  volatile  CO,  is  so  washed  out  of  the 
blood  that  the  CH  is  held  down  in  spite  of  the  continued  production  of 
acid  substances  by  the  muscles.  The  more  strenuous  the  exercise,  the 
less  able  is  the  O,  content  of  the  blood  to  keep  pace  with  the  metabolic 
activity  of  the  muscles,  so  that  relatively  more  and  more  lactic  acid  is 
produced,  necessitating  therefore  a  greater  and  greater  washing  out 
of  CO,. 


370  THE   RESPIRATION 

The  readiness  with  which  C02  can  be  got  rid  of  prevents  the  hormone 
which  excites  the  respiratory  activity  from  continuing  to  act  after  it  is 
no  longer  required.  Provision  for  the  removal  of  a  hormone  after  its 
activity  has  been  displayed  is  of  course  essential  to  efficient  correlation 
of  function,  and  is  seen  in  the  case  of  other  hormones,  such  as  epinephrine 
and  secretin,  whose  discontinuance  of  action  is  effected  by  their  de- 
struction in  the  blood  (see  page  74.5). 

Direct  evidence  that  lactic  acid  is  formed  during  strenuous  muscular 
exercise  in  man  has  been  furnished  by  Ryffel.30  Blood  removed  from  a 
person  immediatey  after  running  at  full  speed  for  about  three  minutes 
contained  70.8  milligrams  of  lactic  acid  per  100  c.c.  of  blood,  the  normal 
amount  being  12.5  milligrams.  Much  of  the  lactic  acid  accumulating  in 
the  blood  is  no  doubt  got  rid  of  by  oxidation,  but  a  large  part  of  it  is 
also  excreted  by  the  urine,  in  which  it  was  found  by  Ryffel  in  consider- 
able amount  after  strenuous  muscular  exertion. 

Finally,  let  us  consider  for  a  moment  the  behavior  of  the  respiratory 
quotient.  This  ratio  rises  early  in  the  muscle  work  (Table  on  page  367), 
indicating  that  more  C02  is  being  excreted  than  02  absorbed.  After  the 
work  is  discontinued,  it  usually  falls  below  the  normal  because  of  retention 
of  C02  to  take  the  place  of  the  lactic  acid  that  is  being  gradually  used  up 
or  excreted.  A  similar  fall  may  sometimes  occur  in  the  respiratory 
quotient  during  muscular  exercise,  if  this  is  continued  for  a  long  time. 
It  probably  indicates  that  a  balance  has  been  struck  between  the  produc- 
tion of  lactic  acid  in  the  muscles  and  the  loss  of  this  substance  by  oxida- 
tion. In  any  case  it  is  a  significant  occurrence,  for  it  coincides  with  the 
great  improvement  in  the  subjective  sensations  accompanying  muscular 
exercise.  It  occurs,  for  example,  at  the  same  time  as  the  appearance  of 
the  "second  wind,"  when  the  circulatory  and  respiratory  distress  expe- 
rienced during  the  earlier  stages  of  strenuous  muscular  exertion  disap- 
pear. The  stages  prior  to  the  second  wind  correspond  to  the  period  when 
considerable  quantities  of  free  C02  are  being  got  rid  of  from  the  blood 
and  are  probably  creating  a  temporary  maladjustment  of  the  CH  which 
acts  on  the  various  medullary  centers.  If  by  forced  breathing  much  of 
this  C02  is  discharged  before  the  muscular  exercise  is  undertaken,  the 
initial  hyperpnea  is  not  nearly  so  marked: 


CHAPTER  XLIH 

THE  CONTROL  OF  R INSPIRATION  (Cont'd) 

PERIODIC  BREATHING 

Types  of  Periodic  Breathing 

In  the  best  known  of  these,  called  Cheyne-Stokes  respiration,  a  period 
of  hyperpnea  supervenes  upon  one  of  apnea,  each  period  following  in 
regular  sequence.  After  an  apneic  period,  the  breathing  begins  at  firsl 
faintly,  gradually  becomes  more  pronounced  until  it  is  markedly  exag- 
gerated, and  then  fades  off  again  to  the  apneic  pause.  Sometimes  the 
apneic  period  is  immediately  followed  by  one  of  intense  hyperpnea,  there 
being  no  gradual  increase  in  the  respiratory  movements.  Between  these 
two  types  all  varieties  of  the  condition  are  met  (Fig.  132). 

The  conditions  in  which  periodic  breathing  occurs  may  be  divided  into 
physiologic  and  pathologic  groups.  Of  the  physiologic  conditions  the 
following  may  be  taken  as  examples:  (1)  Breathing  in  an  atmosphere 
containing  a  deficiency  of  02;  thus,  periodic  breathing  is  very  readily 
produced  in  persons  living  in  rarefied  air.  (2)  The  initial  breathing  fol- 
lowing an  apnea  induced  by  forced  ventilation  of  the  lungs.  In  this  post- 
apneic  periodicity,  the  apneic  periods  may  at  first  be  quite  marked,  but 
as  breathing  returns  they  become  gradually  shorter  and  the  breathing 
intervals  gradually  longer,  until  normal  respiration  is  restored  (Fig. 
131).  (3)  Breathing  through  a  long  tube  having  a  small  vessel  contain- 
ing soda  lime  inserted  between  the  tube  and  the  mouth,  the  whole  capacity 
of  this  vessel  and  tubing  being  about  a  liter.  This  will  cause  periodic 
breathing  in  persons  that  are  susceptible  to  oxygen  deficiency.  Even 
breathing  through  the  tube  -without  soda  lime  will  sometimes  cause  a 
periodic  type  of  breathing  in  such  individuals. 

The  pathologic  conditions  in  which  periodic  breathing  becomes  devel- 
oped are  particularly  those  associated  with  renal  disease  and  cerebral 
hemorrhage.  In  many  of  these  cases,  the  periodic  breathing  does  not 
appear  to  depend  on  the  same  factors  as  are  concerned  in  the  experi- 
mental types.  The  symptoms  would  rather  appear  to  depend  on  some 
influence  of  the  higher  cerebral  (supranuclear)  centers  on  the  respiratory 
center.  At  least  some  other  evidence  of  disturbance  of  the  cerebral  func- 
tions is  always  forthcoming,  such  as  a  slight  paralytic  shock,  and  the 

371 


372  THE    RESPIRATION 

periodic  breathing  is  nearly  always  aggravated  during  sleep.    Many  of 
these  cases  are  greatly  benefited  by  administration  of  caffeine. 

In  both  the  physiologic  and  the  pathologic  groups,  the  breathing  may 
develop  a  periodic  character  only  when  the  person  is  asleep,  and  even 
normal  people,  particularly  infants  or  very  old  people,  may  exhibit  it  to 
a  certain  degree. 


Fig.   132. — Various  types  of  periodic  breathing.      (From  Mosso's  "Life  of  Man  in  the  High  Alps.") 

Causes  of  Periodic  Breathing- 
Great  interest  attaches  to  an  investigation  of  the  causes  of  periodic 
breathing,  but  it  can  not  be  claimed  that  any  perfectly  satisfactory  ex- 
planation has  as  yet  been  offered.  Pembrey31  attributes  it  to  a  diminished 
excitability  (a  raised  threshold)  of  the  respiratory  center  due  to  faulty 
blood  supply,  the  supposition  being  that,  when  thus  suppressed,  the 
normal  CH  of  the  blood  is  unable  to  excite  the  center,  so  that  breathing 
stops.     During  the  resulting  apnea,  CO,  again  accumulates  until  it  has 


THE    CONTROL   OF    THE    RKSl'IRATION  373 

raised  the  Ch  sufficiently  to  excite  the  depressed  center.  Hyperpnea 
Eollows,  causing  a  washing  out  of  the  r02  and  a  resulting  diminution  of 
the  effective  stimulus,  so  that  again  the  center  fails  to  be  stimulated  and 
apnea  supervenes,  and  SO  on.  Support  for  this  explanation  would  appear 
to  he  furnished  by  the  fact  that,  when  patients  exhibiting  periodic  breath- 
ing are  made  to  breathe  an  atmosphere  containing  a  high  percentage  of 
C02,  the  periodicity  of  the  breathing  may  give  place  to  regular  breath- 
ing; a  result  which  may  also  be  obtained  by  making  such  patients 
breathe  in  atmospheres  rich  in  oxygen.  In  the  former  case,  the  stimulus  is 
raised  to  meet  the  depressed  excitability  of  the  center;  in  the  latter,  the 
excitability  of  the  center  is  increased  because  of  better  blood  supply 
so  that  it  is  enabled  to  react  to  the  diminished  stimulus.  But  even 
granted  that  the  excitability  of  the  center  is  depressed,  it  is  difficult  to 
see  why  this  should  occasion  a  periodic  type  of  breathing  unless  we  as- 
sume that  it  is  only  when  stimulus  (i.  e.,  CH  of  blood)  and  threshold  of 
excitability  of  the  center  are  adjusted  at  a  certain  physiologic  level  that 
smooth  and  continuous  action  can  go  on. 

Haldane  and  his  school  aver  that  there  is  no  permanent  alteration  in 
the  excitability  of  the  center,  but  that  the  periodicity  is  due  to  several 
causes,  which  do  not  always  operate  to  the  same  degree  in  the  different 
conditions  in  which  such  periodicity  exists.  To  study  these  causes  tin- 
exact  conditions  existing  in  the  various  types  of  periodic  breathing  that 
can  be  produced  experimentally  in  man  have  been  investigated. 

The  most  simple  to  consider  first  is  the  periodic  breathing  that  is 
produced  in  a  person  susceptible  to  02  want,  by  breathing  through  a  tube 
and  bottle  (of  a  total  capacity  of  1  liter),  containing  soda  lime. 
In  such  a  case  no  outside  air  enters  the  lungs,  for  what  Ave  have  really 
done,  besides  providing  for  the  absorption  of  C02,  is  greatly  to  prolong 
the  dead  space.  The  oxygen  tension  of  the  rebreathed  air,  therefore, 
quickly  falls,  until  at  last  a  point  is  reached  at  which  the  respiratory  cen- 
ter is  directly  stimulated  by  02  deprivation, .  as  we  have  seen  it  to  be 
when  this  falls  to  a  sufficiently  low  level  (see  page  350).  The  deep 
breaths  (hyperpnea)  which  follow,  being  of  greater  volume  than  1000 
c.c,  cause  outside  air  to  be  inspired  so  that  the  02  want  is  made  good 
and  the  hyperpnea  again  disappears,  possibly  to  the  extent  of  apnea,  for 
now,  in  consequence  of  a  coincident  "washing  out"  of  C02,  there  has 
been  a  lowering  of  the  CH  of  the  blood  below  the  threshold  value.  During 
the  apnea  the  02  is  rapidly  used  up,  till  a  point  is  reached  at  which  the 
center  again  becomes  excited.  In  such  an  experiment  the  effect  of  02 
want  becomes  very  marked,  as  shown  by  the  intense  cyanosis  which 
develops. 

That  breathing  under  these  conditions  should  be   periodic   and  not 


374  THE    RESPIRATION 

merely  show  a  steadily  increasing  hyperpnea  is  probably  due  to  the  un- 
equal rates  at  which  the  02  and  C02  tensions  change  in  the  blood.  Be- 
cause of  a  "buffer  action"  the  latter  fluctuates  much  less  than  the  for- 
mer. Another  cause  for  the  periodicity  is  no  doubt  the  delay  between 
the  gas  exchange  in  the  lungs  and  the  arrival  of  the  blood  in  the  brain. 
When  the  02  tension  of  the  blood  supplying  the  respiratory  center  falls 
to  so  low  a  level  that  excitation  of  the  center  occurs,  the  resulting  in- 
creased breathing  aspirates  outside  02  into  the  alveoli.  After  a  moment 
or  so,  the  02  is  carried  by  the  blood  to  the  center,  so  that  its  stimula- 
tion by  02  deficiency  is  removed,  and  it  is  left  in  a  condition  in  which 
it  fails  to  discharge  any  impulses,  since  there  is  a  subnormal  CH  of  the 
blood  as  a  consequence  of  the  lowering  of  the  C02  tension  produced  by 
the  hyperpnea.  A  little  time  must  now  elapse  before  the  C02  again 
rises  or  the  0,  falls  sufficiently  to  excite  the  center. 


Fig.    133. — Quantitative  record  of  breathing  air  through  a  tube  260  cm.   long  and  2  cm.  in  diameter. 

(From  Douglas  and  Haldane.) 

A  similar  although  less  marked  degree  of  periodic  breathing  can 
sometimes  be  obtained  by  merely  respiring  through  a  long  tube  without 
any  provision  for  the  absorption  of  C02.  In  this  case  it  is  more  difficult 
to  explain  the  cause  of  the  periodic  breathing,  but  that  the  main  factor 
concerned  is  one  of  0,  deprivation  is  evidenced  by  the  fact  that  in  this 
as  in  the  previous  experiment,  the  periodic  nature  of  the  respiration  is 
immediately  changed  to  the  regular  breathing  if  02  is  introduced  into 
the  tube.  The  interest  of  the  experiment  lies  in  the  fact  that  a  similar 
relative  elongation  of  the  dead  space  is  probably  accountable  for  the 
periodic  breathing  seen  in  the  winter  sleep  of  hibernating  animals.  Dur- 
ing this  condition,  on  account  of  the  depression  of  metabolism  less  02 
is  required  and  less  C02  is  produced,  so  that  the  exchange  of  gases 
through  the  pulmonary  endothelium  is  greatly  diminished.  The  dead 
space,  however,  remains  of  the  same  capacity,  which  amounts  to  the 
same  thing  as  if  the  latter  had  been  prolonged  under  unchanged  con- 
ditions of  pulmonary  gas  exchange. 


Till     CONTROL   OF   Till;   RESPIRATION  375 

The  explanation  for  other  types  of  experimental  periodic  breathing  is 
much  less  satisfactory,  Important  evidence  that  changes  occurring  in 
the  tensions  of  Oa  and  CO,  in  the  alveolar  air  and  therefore  in  the 
arterial  blood  of  the  respiratory  center  are  largely  responsible  for  periodic 
breathing  lias  been  secured  by  studying  the  condition  that  develops  after 
a  period  of  apnea  produced  by  voluntary  forced  breathing.  The  results 
of  Buch  observations  are  given  in  the  curve  shown  in  Fig.  131. 

The  thin  line  represents  the  02  tension  of  the  alveolar  air,  the  thick 
lino  the  C02  tension.  The  double  line  running  across  the  chart  repre- 
sents the  average  tension  of  C02  during  quiet  normal  breathing.  The 
respiratory  movements  are  represented  by  the  tracing  at  the  foot  of 
the  curve  along  the  abscissa.  It  Mill  be  observed  that  the  oxygen  ten- 
sion falls  very  rapidly  during  the  apneic  period,  until  just  before  breath- 
ing recommences  it  may  be  as  Ioav  as  30-35  mm.  Hg  instead  of  the  nor- 
mal of  about  95.  Meanwhile  the  C02  tension  rises  from  the  very  low 
level  of  12  mm.,  at  first  very  rapidly,  then  more  gradually,  although, 
when  breathing  recommences,  it  has  not  yet  gained  the  normal  level. 
As  a  result  of  the  first  periods  of  breathing,  the  0,  tension  suddenly 
shoots  up,  but  the  C02  falls  only  slightly.  During  the  next  apneic  stage 
the  O,  quickly  comes  down  again,  and  the  CO,  rises  so  as  almost  to  at- 
tain normal  tension  before  breathing  again  supervenes.  As  the  apneic 
periods  subsequently  become  less  pronounced,  the  C02  tension  comes  to 
stand  almost  at  its  normal  level,  whereas  considerable  variations  in  the 
02  tension  continue  to  occur. 

Several  interesting  features  of  these  results  demand  attention.  In 
the  first  place,  it  is  plain  that  the  body  is  possessed  of  some  mechanism 
by  which  it  can  prevent  great  fluctuations  in  the  CO,  tension  of  the 
blood,  whereas  towards  02  no  such  "buffer  action"  is  displayed.  It  will 
further  be  observed  that  the  C02  tension  of  the  alveolar  air  rises  very 
rapidly  during  the  first  part  of  the  apneie  period,  and  then  more  grad- 
ually, the  explanation  being  that  during  the  forced  breathing  the  CO, 
has  been  washed  out  from  the  blood  but  not  from  the  body  as  a  whole. 

At  first  sight  one  might  attribute  the  periodicity  to  the  same  cause 
as  that  operating  during  breathing  through  a  long  tube  with  soda  lime — 
namely,  to  oxygen  deficiency.  But  this  explanation  is  untenable,  be- 
cause the  periodicity  remains  evident  for  some  time  after  all  possibility 
of  direct  stimulation  of  the  center  of  0,  deficiency  is  over.  A  possible 
clue  is  furnished  by  the  fact  that  breathing  returns  while  the  CO,  ten- 
sion is  still  considerably  below  its  normal  level.  The  return,  as  we  have 
seen,  is  accounted  for  by  the  appearance  of  lactic  acid,  and  if  we  assume 
that  this  has  occurred  particularly  in  the  respiratory  center  itself,  a 
slight  degree  of  hyperpnea  will  be  excited,  which  by  supplying  0,  will 


376  THE   RESPIRATION 

quickly  oxidize  the  lactic  acid,  so  that  the  still  slightly  subnormal  CM 
of  the  blood  is  unable  to  excite  the  center.  Apnea  therefore  supervenes 
and  lasts  until  lactic  acid  has  again  accumulated  in  the  center.  To  ex- 
plain why  local  accumulation  of  lactic  acid  in  the  center  should  produce 
a  periodic  type  of  breathing,  we  must  further  assume  that  there  is  con- 
siderable delay  between  the  moment  at  which  equilibrium  of  the  gases 
in  the  blood  and  alveolar  air  becomes  established  and  that  at  which 
the  blood  arrives  at  the  respiratory  center.  This  delay  is  caused  by 
the  slowing  of  the  bloodflow  on  account  of  the  absence  of  respiratory 
movements. 

Emphasis  is  placed  on  the  fact  that  it  is  in  the  center  itself  and  not 
in  the  blood  that  the  lactic  acid  becomes  oxidized  by  the  excess  of  02, 
because  lactic  acid  is  known  to  disappear  slowly  under  these  conditions 
from  isolated  blood,  but  to  do  so  very  quickly  from  tissues  such  as  muscle, 
and  presumably  therefore  also  from  nervous  tissue. 

In  support  of  the  above  explanation  it  has  been  found  that,  if  toward 
the  end  of  the  forced  breathing  the  lungs  are  filled  with  sufficient  02 
so  that  the  tension  of  this  gas  in  the  alveoli  is  not  lower  than  120  mm. 
Hg,  breathing  is  regular  in  type  when  it  returns,  and  the  C02  tension 
of  the  alveolar  air  is  several  millimeters  above  instead  of  below  the  nor- 
mal stimulating  level. 

To  sum  up,  the  periodic  character  of  the  breathing  supervening  on 
a  period  of  apnea  may  be  explained  as  follows:  Under  ordinary  condi- 
tions of  breathing  and  barometric  pressure  the  02  tension  of  the  blood 
is  sufficient  between  normal  respirations  to  prevent  any  accumulation  of 
lactic  acid  in  the  respiratory  center,  so  that  the  stimulus  afforded  by  the 
Ch  of  the  blood  produces  a  constant  effect.  During  the  apnea  which 
supervenes  upon  forced  breathing,  lactic  acid  accumulates  in  the  center, 
causing  this  to  respond  to  the  gradually  rising  CH  of  the  blood  before  the 
latter  has  reached  its  physiologic  level.  The  hyperpnea  thus  excited 
does  not,  however,  bring  about  a  prompt  oxidation  of  the  lactic  acid 
in  the  center  or  a  lowering  of  the  CH  of  the  blood  circulating  through  it, 
because  more  time  than  usual  is  taken  for  the  blood  to  get  from  the 
lungs  to  the  brain  on  account  of  the  absence  of  respiratory  movements. 
When  the  aerated  blood  does  reach  the  respiratory  center,  the  excess  of 
02  which  it  contains  oxidizes  the  lactic  acid  so  that  apnea  supervenes, 
and  the  lactic  acid  again  accumulates,  although  not  now  so  much  as 
before  because  of  the  gradually  rising  CH  of  the  blood  itself.  The  essen- 
tial factor  in  the  causation  of  periodic  breathing  is  therefore  a  delayed 
mass  movement  of  the  blood  from  the  pulmonary  capillaries  to  the  re- 
spiratory center.     The  delay  may  be  caused  by  cessation  of  the  respira- 


THE   CONTROL   OF   THE   RESPIRATION  377 

tory  movement,  as  in  postapneic  periodicity,  or  by  some  pathologic  cir- 
culatory disturbance. 

Periodic  breathing  is  produced  by  Forced  respiration  more  readily  in 
rarefied  air  than  at  sea  level.  It  was  found  by  Douglas,20  after  breath- 
ing Eorcibly  for  one  minute  at  sea  level,  that  the  breathing  when  it 
returned  showed  8  to  10  different  periods  of  apnea  and  hyperpnea.  On 
repetition  of  the  experiment  at  an  altitude  giving  a  barometric  pres- 
sure of  600  mm.,  25  such  periods  followed  the  apnea;  at  a  height  cor- 
responding to  520  mm.,  40  periods.  Indeed,  at  high  altitudes  periodic 
breathing  may  be  brought  about  by  the  slightest  alteration  in  normal 
respiration;  even  taking  a  deep  breath  may  be  sufficient  to  cause  distind 
periodicity  in  the  succeeding  respirations,  and  in  many  persons  living 
at  high  altitudes  periodic  breathing  is  very  apt  to  occur  during  sleep. 
As  in  pathologic  cases  exhibiting  Cheyne-Stokes  respiration,  the  peri- 
odic breathing  at  high  altitudes  can  be  immediately  removed  by  inspir- 
ing oxygen. 

We  have  devoted  considerable  space  to  a  discussion  of  these  extremely 
difficult  problems  in  the  hope  that  clinical  observers,  by  becoming  ac- 
quainted with  the  purely  experimental  work,  may  be  in  a  position  to 
conduct  more  searching  investigations  as  to  the  cause  of  Cheyne-Stokes 
and  other  pathologic  forms  of  periodic  breathing. 


CHAPTER  XLIV 
RESPIRATION  BEYOND  THE  LUNGS 

Up  to  the  present  our  studies  in  respiration  have  concerned  the  various 
mechanisms  involved  in  bringing  about  a  constant  change  in  the  com- 
position of  the  alveolar  air.  We  must  now  consider  the  nature  of  the 
means  by  which  the  oxygen  is  conveyed  to  the  tissues  and  the  C02  re- 
moved from  them. 

In  the  first  place,  it  is  important  to  note  that  it  is  not  for  purposes 
of  oxidation  in  the  blood  itself  that  the  02  is  required.  In  its  respiratory 
function  this  fluid  serves  as  a  transporting  agency  between  the  lungs 
and  the  tissues,  in  which  reside  the  furnaces  of  the  body  that  con- 
sume the  0,  and  produce  the  C02.  This  does  not  imply  that  there  is  no 
oxidation  in  the  blood  itself;  indeed,  we  should  expect  a  certain  degree 
of  oxidation  because  of  the  fact  that  the  blood  contains  some  living 
cells — the  leucocytes.  It  is  scarcely  necessary  nowadays  to  offer  evi- 
dence for  the  foregoing  conclusion.  One  well-known  experimental  proof 
consists  in  replacing  the  Mood  in  a  frog  with  physiologic  saline  solution 
and  then  subjecting  the  frog  with  the  saline  in  its  blood  vessels  to  an 
atmosphere  of  pure  02,  when  it  will  be  found  that  the  animal  continues 
to  absorb  the  normal  amount  of  02  and  exhale  the  normal  amount  of 
( !( )L>.     It  respires  normally  without  any  blood  in  the  blood  vessels. 

In  order  that  this  transportation  of  gases  between  the  lungs  and  the 
1  issues  may  be  efficiently  performed,  the  blood  must  be  provided  with 
means  for  carrying  adequate  amounts  of  gases  to  supply  the  requirements 
of  the  tissues,  both  during  rest  and  during  their  varying  degrees  of 
activity.  Not  only,  therefore,  must  the  02  and  C02  capacity  of  the 
blood  be  very  considerable,  but  it  must  be  capable  of  very  rapid  adjust- 
ment from  time  to  time. 

Our  problem  naturally  resolves  itself  into  three  parts:  (1)  the  call 
of  the  tissues  for  oxygen  (Barcroft)  ;  or,  as  it  is  styled,  tissue  or  internal 
respiration ;  (2)  the  mechanism  by  which  the  blood  transports  the  proper 
amounts  of  gases  to  meet  the  requirements  of  the  tissues;  and  (3)  the 
mechanism  by  which  the  blood  gases  are  exchanged  in  the  lungs — ex- 
ternal respiration.  For  convenience,  however,  we  shall  change  this  nat- 
ural order  and  consider  the  transportation  of  the  gases  first. 

378 


RESPIRATION    BEYOND   THE    LUNGS  379 

THE  TRANSPORTATION  OF  GASES  BY  THE  BLOOD 

The  Transportation  of  Oxygen 

It  is  plainly  not  by  mere  solution  in  the  plasma  of  the  blood  that  the 
transportation  of  02  occurs,  for  at  the  partial  pressure  of  this  gas  ex- 
isting in  the  alveolar  air  at  the  temperature  of  the  body  the  amount,  that 
could  be  dissolved  in  the  blood  -would  be  only  one-fortieth  of  that  which 
is  actually  found  to  be  present.  If  there  were  only  plasma  in  the  blood 
vessels,  it  would  require  a  volume  of  fluid  amounting  to  150  kilograms 
or  more  in  order  to  convey  the  necessary  amount  of  0.,  from  the  lungs 
to  the  tissues;  that  is,  the  contents  of  the  vascular  system  would  weigh 
twice  as  much  as  the  average  weight  of  a  man. 

The  substance  that  carries  the  02  in  the  blood  is  the  hemoglobin,  Avhich 
may  be  described  as  a  highly  complex  iron  compound  of  protein  espe- 
cially evolved  for  the  purpose  of  transporting  02.  In  some  of  the  lower 
animals  other  compounds  exist  in  the  blood  for  this  purpose,  but  none 
of  them  is  to  be  compared  in  its  efficiency  Avith  hemoglobin.  They  are 
merely  poor  imitations  of  it. 

Regarding  the  conditions  under  which  hemoglobin  combines  with  or 
delivers  up  02,  the  first  question  that  presents  itself  is  whether  or  not 
the  reaction  is  a  strictly  chemical  one.  If  so,  a  definite  amount  of  02 
must  be  capable  of  combining  with  a  definite  amount  of  hemoglobin.  It 
is  impossible  to  secure  hemoglobin  of  sufficient  purity  to  test  this  rela- 
tionship directly  on  hemoglobin  itself,  so  that  we  must  test  it  indirectly 
by  examining  the  combining  equivalent  between  0,  and  that  portion  of 
the  hemoglobin  molecule  upon  which  the  combining  power  depends.  This 
is  the  part  of  the  molecule  containing  iron.  Now,  if  we  compare  the 
amount  of  02  which  hemoglobin  can  take  up  with  the  amount  of  iron 
present  in  the  hemoglobin,  we  shall  find  that  one  atom  of  iron  becomes 
combined  with  two  atoms  of  02.  Evidently,  then,  we  are  here  dealing 
with  a  definite  chemical  reaction  occurring  between  the  02  and  the  iron 
of  the  hematin  portion  of  the  hemoglobin.  This  relationship  is  known 
as  "the  specific  oxygen  capacity  of  hemoglobin.  " 

In  showing  that  the  union  of  02  and  hemoglobin  occurs  according  to 
chemical  laws,  we  throw  into  prominence  consideration  of  the  mechanism 
by  which  the  02  combined  with  hemoglobin  in  the  blood  is  rapidly  de- 
livered up  in  the  capillaries  so  as  to  supply  the  tissues  with  their  require- 
ment, and  is  then  as  rapidly  recombined  again  in  the  lungs.  Moreover, 
we  must  reconcile  facts  implied  by  the  idea  of  a  specific  02  capacity  with 
the  well-known  observation  that  the  hemoglobin  in  the  circulation  is 
usually  united  with  considerably  less  02  than  the  total  amount  possible. 


380  THE    RESPIRATION 

In  other  words,  we  must  recognize  that,  although  it  is  essentially  a 
chemical  reaction,  the  combination  of  02  with  hemoglobin  is  greatly  in- 
fluenced by  other  factors,  and  that  it  is  these  that  are  likely  to  be  of 
physiologic  importance. 

In  order  to  understand  the  conditions  under  which  hemoglobin  will 
take  up  and  give  off  02  in  the  animal  body,  we  must  study  the  combining 
power  of  hemoglobin  when  it  is  exposed  to  different  partial  pressures 
of  02  (for  laws  governing  this,  see  page  33G).  In  the  blood,  the  ex- 
tremes of  the  partial  pressure  of  02  are  represented,  at  the  one  end,  by 
that  in  the  alveolar  air,  which  we  have  seen  to  be  about  100  mm.  Hg, 
and  at  the  other,  by  that  existing  in  the  tissues,  such  as  muscle,  which 
has  been  shown  to  be  not  more  than  19  or  20  mm.  Hg.  We  must  further 
bear  in  mind  that  the  02  in  its  passage  from  the  alveolar  air  to  the  hemo- 
globin and  from  the  hemoglobin  to  the  tissues,  is  transmitted  in  solution 
through  the  plasma;  that  is,  so  far  as  the  supply  of  02  to  the  tissue  cells 
is  concerned,  the  plasma  serves  as  the  immediate  source.  Since  the  tis- 
sues are  using  up  02  at  a  very  great  speed,  especially  when  active,  and 
are  thus  tending  to  lower  the  tension  of  0,  in  the  plasma,  favorable  con- 
ditions have  to  be  created  whereby  the  hemoglobin  liberates  02  at  the 
same  rate  as  that  at  which  it  is  leaving  the  plasma.  In  brief,  it  is  the 
02  tension  of  the  plasma  in  the  tissue  capillaries  that  is  the  important 
factor,  the  hemoglobin  merely  serving  as  a  storehouse,  which  delivers 
its  O,  at  just  such  a  rate  as  to  maintain  the  plasma-oxygen  tension  at 
a  constant  level.  It  is  obviously  of  the  greatest  importance  that  we 
should  understand  how  this  mechanism  of  an  adequate  plasma-oxygen 
tension  is  maintained. 

Methods  of  Investigation. — We  must  remember  that  the  combination 
of  02  and  hemoglobin,  being  a  definite  chemical  reaction,  will  be  re- 
versible, and  must,  therefore,  obey  the  laws  of  mass  action  (see  page 
23)  according  to  the  equation:  Hb  -f-  02^±Hb02.  In  order  to  ascertain 
the  position  of  the  balance  of  this  equation  at  different  partial  pressures 
of  02, — that  is,  the  relative  quantities  of  oxy-  and  reduced  hemoglobin 
formed  in  a  solution  of  hemoglobin  when  this  is  shaken  with  0,  at  differ- 
ent pressures, — we  may  proceed  as  follows:  A  few  c.c.  of  the  hemoglobin 
solution  are  placed  in  each  of  a  series  of  vessels  called  tonometers,  like 
those  shown  in  Fig.  134.  In  addition  to  the  hemoglobin  solution,  each 
tonometer  contains  a  mixture  of  nitrogen  and  02  in  different  propor- 
tions. Suppose  we  use  six  vessels  and  in  No.  1  have  pure  nitrogen;  in 
No.  2,  nitrogen  containing  5  mm.  partial  pressure  of  02;  in  No.  3,  10 
mm. ;  in  No.  4,  20 ;  in  No.  5,  50 ;  and  in  No.  6,  100.  We  now  rotate  the 
tonometers  in  a  water-bath  at  body  temperature  for  about  twenty  min- 
utes, so  that,  by  the  formation  of  a  thin  film  of  hemoglobin  solution  over 


RESPIR  \'l'Ki\    BEYOND   THE    LUNGS 


381 


the  walls  of  the  vessel,  perfed  equilibrium  between  the  atmosphere  and 
the  fluid  may  be  attained  (.see  page  338).  A  measured  quantity  of  hemo- 
globin solution  (0.1  or  1.0  c.c.)   is  then   removed   Erom  each  tonometer 


Fig.    134. — Barcroft's   tonometer   for   determining   the   curve    of   absorption    of   oxygen    by    hemoglobin 
or  blood.      (From   Starling's  Physiology.) 

and  placed,  together  with  some  very  dilute  ammonia  to  lake  the  blood. 
in  one  of  the  small  bottles  of  the  differential  manometer,  shown  in  Fig. 
135.*  This  manometer  consists  in  principle  of  a  graduated  U-shaped 
tube  of  narrow  bore,  containing  clove  oil,  the  free  end  of  the  U-tube 


Fig.    135. — Barcroft's    differential    blcod    gas    manometer.      The    capillary    U-tube    contains    clove    oil. 
The  pockets  on  the  sides  of  the  blood  bottles  should  be  deeper.     For  manipulation  see  context. 

being  connected  with  small  bottles  provided  with  some  device  so  that 
two  fluids  can  be  placed  in  each  of  them  but  kept  unmixed  until  the 
bottle  is  violently  shaken.     The  three-way  stopcock  between  the  small 


'The  blood-gas   manometers  are  made   in   two  sizes   for  use   with   1    c.c.   and   0.1    c.c.   quantities  of 
blood,  respectively.     The  results  with  these  small  quantities  are  as  accurate  as  with  larger  amounts. 


382 


THE   RESPIRATION 


bottles    and    the    manometer   serves   to    permit    communication    of   the 
manometer  with  the  outside  air. 

An  equal  quantity  of  hemoglobin  solution  that  has  been  saturated 
with  oxygen — i.  e.,  oxyhemoglobin — is  placed  in  the  bottle  on  the  other 
end  of  the  manometer  tube  from  that  containing  the  bottle  with  the  un- 
saturated hemoglobin  solution.  The  bottles  having  been  attached  to 
the  manometer  with  the  stopcocks  open  to  the  outside,  the  apparatus 
is  placed  in  a  water-bath  until  the  temperature  conditions  are  constant. 
The  manometers  are  then  closed  to  the  outside  air  and  the  bottles  are 
shaken  in  order  that  the  hemoglobin  solution  that  is  unsaturated  with 
0,  may  take  up  02  from  the  atmosphere  in  the  bottle  until  it  becomes 


Fig.  136. — Barcroft  blood  gas  manometer.  This  form  can  be  used  either  as  a  differential 
manometer  (page  390)  or  for  direct  measurement  of  pressure.  For  the  latter  purpose  one  bottle 
is  removed  and  the  pressure  of  gas  generated  in  the  other  bottle  is  measured  by  the  height  to 
which  it  raises  the  clove  oil  in  the  distal  tube  of  the  manometer,  the  meniscus  in  the  proximal 
limb  being  readjusted  to  its  original  level  by  compression  with  the  brass  screw  of  the  rubber  tube 
shown   in   the   center. 


saturated.  The  resulting  shrinkage  in  the  volume  of  the  atmosphere 
on  the  side  of  the  unknown  hemoglobin  solution  causes  the  clove  oil 
meniscus  to  move  towards  that  side,  the  degree  of  movement  being  pro- 
portional to  the  initial  unsaturation  of  the  hemoglobin.  The  manometer 
tubes  are  then  again  brought  into  communication  with  the  atmosphere 
so  that  the  meniscus  of  clove  oil  may  move  back  to  its  old  level,  and  the 
bottle  with  saturated  hemoglobin  is  removed  from  the  manometer  and  a 
drop  or  two  of  a  saturated  solution  of  potassium  ferricyanide  placed 
in  the  separate  compartment  of  the  bottle  without  allowing  it  to  mix 
with  the  hemoglobin.     The  bottle  is  then  reattached,  the  temperature 


4i    (J 


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10       20 


40 


100 


mm.  pressure 


Percentage  saturation 
with  oxygen 


80       90       100 

Oxygen  pressure 
mm. 


Fig.  137. — Upper  left  hand,  percentage  saturation  of  hemoglobin  with  oxygen  at  37"  C.  cor- 
responding  to    oxygen   pressures   of   0,    10,    20,    40   and    100   mm.    of   oxygen,    respectively. 

Upper  right   hand,  the  same  spaced   with  the   oxygen   pressure  as  the  abscissae. 

Lower  figure,  dissociation  curve  representing  the  equilibrium  between  oxygen,  oxyhemoglobin 
(red)    and   reduced   hemoglobin    (purple).      (From  Joseph   Barcroft.) 


RESPIRATION    BEYOND   THE    LUNGS  383 

conditions  readjusted,  the  manometer  closed  off  from  the  ouside  air, 
and  the  apparatus  again  shaken  so  thai  the  ferricyanide  mixes  with  the 
hemoglobin  solution.  This  drives  off  all  the  02  from  the  oxyhemoglobin 
solution,  and,  therefore,  raises  the  pressure  in  tin-  atmosphere  of  thai 
bottle  so  that  the  elove  oil  moves  to  the  opposite  side  of  the  manom- 
eter, the  degree  of  displaeement  being  proportional  to  the  amount  of 
oxyhemoglobin. 

We  have  now  all  the  neeessary  data  for  estimating  the  relative  amounts 
of  redueed  hemoglobin  in  the  hemoglobin  solution  as  removed  from  the 
tonometers,  for  it  is  plain  that  the  second  estimation,  as  described  above, 
tells  us  Iioav  much  oxyhemoglobin  might  have  been  formed  had  all  the 
hemoglobin  been  saturated  and  the  first  one,  how  much  0,  had  yet  to  be 
taken  up  by  the  original  hemoglobin  solution  to  produce  saturation. 

The  Dissociation  Curve. — The  next  step  is  to  plot  the  results  obtained 
from  the  various  hemoglobin  solutions  in  the  form  of  a  curve.  This  is 
known  as  the  dissociation  curve  of  hemoglobin.  It  is  plotted  with  the 
relative  percentages  of  reduced  and  oxyhemoglobin  in  each  of  the  solu- 
tions along  the  ordinates,  and  the  partial  pressures  of  02  in  millimeters 
of  mercury  to  which  they  were  exposed  along  the  abscissae.  The  curve 
thus  drawn  is  exactly  of  the  same  shape  as  that  which  would  be  pro- 
duced if  we  were  to  place  the  tonometers  in  a  row  at  distances  from  one 
another  corresponding  to  the  partial  pressure  of  (X  which  each  con- 
tained, and  then  to  mark  on  each  tonometer  the  relative  amounts  of 
reduced  and  oxyhemoglobin  found  in  the  solutions  after  shaking.  A 
line  joining  these  marks  on  the  tonometers  would  then  exactly  corre- 
spond to  the  curve  drawn  by  the  method  described  above.  This  will  be 
clear  from  the  accompanying  figure  from  Barcroft's  book   (Fig.   137). 

In  such  a  chart  the  space  below  the  curve  can  be  taken  to  represent 
the  percentage  of  oxyhemoglobin  (red  in  chart),  and  that  above  it  of 
reduced  hemoglobin  (blue  in  chart),  at  the  varying  partial  pressures  of 
02  which  are  indicated  along  the  abscissae  as  being  contained  in  the  at- 
mosphere of  the  tonometers,  and  which  must  be  proportional  to  the 
partial  pressure  of  02  in  the  solution  in  which  the  hemoglobin  is  dis- 
solved. 

Difference  between  Curves  of  Blood  and  Hemoglobin  Solutions. — The 
curve  obtained  from  pure  hemoglohin  solutions  is  very  far,  however, 
from  clearing  up  the  problem  as  to  how  the  blood  absorbs  and 
discharges  02.  On  the  contrary,  it  makes  this  problem  appear 
all  the  more  difficult,  for,  according  to  the  curve  (Fig.  137)  the  hemo- 
globin is  already  more  than  half  combined  with  02  at  a  partial  pressure 
of  this  gas  of  no  more  than  10  mm.  Hg,  which  means  that  in  the  low 
partial  pressure  of  02  existing  in  the  capillaries  the  oxyhemoglobin,  in- 


384 


THE    RKSP1RATIOX 


stead  of  readily  yielding  up  its  load  of  02,  would  greedily  retain  prac- 
tically the  whole  of  it.  The  curve,  in  other  words,  would  satisfactorily 
explain  why  hemoglobin  should  readily  absorb  02  from  the  alveolar  air, 
but  would  fall  far  short  of  explaining  how  this  02  is  readily  released 
when  it  is  required  in  the  tissues.  Obviously  there  is  some  artificial  con- 
dition present  in  the  above  experiment  which  can  not  obtain  in  the  nat- 
ural environment  of  the  blood. 


•00 
<?0 

do 

70 
60 
50 
HO 
30 
2.0 

10 
0 


z/ 

a/ 

rB/ 

d/ 

W     ZO     30     HO     50     bO      10     30    10    100 


Fig.    138. — Average    dissociation    curves. 


Ordi nates — Percentage   saturation   of   hemoglobin   with    oxygen. 

Abscissie — Tension    of    oxygen    in    mm.    of    mercury. 

Curve   A — Degree   of   saturation   of   pure   hemoglobin   solutions   at   varying  pressures. 

Curve  B — Disregard    this    curve. 

Curve  C — Effect   of   20   mm.    C02   pressure   on   above   solution. 

Curve  D — The  saturation  curve  in  normal  blood  at  40  mm.  carbon  dioxide  pressure. 

Since  hemoglobin  takes  up  02  in  proportion  to  its  iron,  it  can  not  be 
because  of  changes  in  the  02  combining  part  of  the  hemoglobin  itself 
that  blood  and  pure  hemoglobin  solutions  have  dissimilar  dissociation 
curves,  but  rather  because  of  differences  in  the  environment  in  which  the 
hemoglobin  acts.  That  this  is  so  can  be  readily  shown  by  plotting  the 
dissociation  curve,  not   for  a  hemoglobin  solution,  but  for   blood  itself 


RESPIRATION    BEYOND   THE    LUNGS 


:;s:, 


(/>  in  Pig.  138).  The  results  are  very  different.  At  a  partial  pressure 
of  0.,  of  about  60  mm.  Eg  that  is,  a  lower  pressure  than  exists  in  the 
lung  alveoli  (100  mm.)— the  blood  becomes  nearly  saturated  with  02, 
whereas  at  pressures  below  50  mm.  it  readily  loses  02,  so  that  at  10  mm. 
there  is  nearly  complete  reduction. 

The  question  is:   What  are  the  environmental  conditions  under  which 
the  hemoglobin  in  the  blood  so  alters  its  combining  power  for  02  as  to 


100 


60 


70 


100 


20  30  40  50 

Fig.    139. — Dissociation    curves    of    hemoglobin. 

Ordinates — Percentage    saturation   of   hemoglobin. 
Abscissa — Tension    of    oxygen   in    mm.    of   mercury. 

I.  Dissociation   curve   of    hemoglobin    dissolved    in    water. 

II.  Dissociation   curve    of    hemoglobin    dissolved    in    7%    NaCl. 

III.  Dissociation    curve    of    hemoglobin    dissolved    in    9%     KG. 
Temperature   37-38°    C.      (From   Joseph    Barcroft.) 

produce  such  a  difference  in  the  dissociation  curve?  By  experimenting 
with  hemoglobin  solutions,  three  such  factors  have  been  found  to  come 
into  play:  (1)  the  presence  of  inorganic  salts,  (2)  the  hydrogen-ion  con- 
centration (C02  tension)  of  the  solution,  and  (3)  the  temperature.  If 
hemoglobin  is  dissolved  in  water  containing  the  varitfus  salts  of  plasma 
in  the  same  proportion  as  in  blood  (artificial  plasma),  the  dissociation 
curve  will  be  found  to  change  so  as  to  resemble  that  of  blood  (Fig.  139). 


386 


THE    RESPIRATION 


Since  the  plasmas  of  different  animals  contain  different  proportions  of 
salts,  the  artificial  plasma  required  to  secure  the  result  is  not  always  the 
same.  It  differs,  for  example,  for  the  dog  and  man.  Potassium  salts 
are  particularly  efficient  in  causing  hemoglobin  to  absorb  02.  The  in- 
fluence of  varying  hydrogen-ion  concentrations  of  the  solution  may 
be  conveniently  studied  by  adding  varying  percentages  of  C02  to  the 
gas  mixture  in  the  tonometers,  when  it  will  be  found  that  the  curve  be- 
comes lowered  in  proportion  to  the  amount  of  C02  present.  This  is  shown 
in  Fig.  140. 

The  effect  of  temperature  on  the  dissociation  curve  is  twofold:  (1)  on 
the  rate  with  which  equilibrium  is  established  at  the  given  partial  pres- 


100 
90 
80 
70 
60 
50 
40 
30 


20 


*a 


Oy 

-~ — '    '■ 

1 

7           / 

$/ 

1 

/          / 

w 

20       30       40       GO 


70       80       90      100 


Fig.    140 — Dissociation  curves  of  human  blood,  exposed  to  0,   3,   20,   40  and  90  mm.   CO«.     Ordinate, 
percentage   saturation.     Abscissa,    oxygen   pressure.      (From    Joseph    Barcroft.) 

sure  of  02,  and  (2)    on  the  position  of  the  curve;  the  lower  the  tempera- 
ture, the  higher  the  curve. 

The  Rate  of  Dissociation. — Though  it  is  now  clear  that  the  three  con- 
ditions— namely,  saline  content,  CH,  and  temperature — are  capable  of 
altering  the  dissociation  curve  of  a  pure  hemoglobin  solution  so  as  to 
make  it  correspond  with  that  of  blood,  this  does  not  entirely  solve  our 
problem,  for  we  have  yet  to  show  how  the  cooperation  of  these  forces 
renders  it  possible  for  the  rate  at  which  hemoglobin  takes  up  02  in 
the  lungs  to  correspond  exactly  with  that  at  which  it  gives  up  its  02 
to  the  tissues.  To  study  this  problem  a  somewhat  different  kind  of 
experiment  must  be  undertaken.  The  hemoglobin  solution  is  placed  in 
a  tube  and  the  gas  mixture  slowly  bubbled  through  it,  samples  of  the 
solution  being  removed  at  intervals  for  analysis  in  the  differential  blood- 


RESPIRATION    BEYOND   THE   LUNGS 


387 


gas  apparatus.  To  obtain  the  rate  of  oxidation,  a  mixture  of  N2  or  H2 
and  Oa  is  bubbled  through  the  blood  with  the  partial  pressure  of  the 
0,  the  same  as  thai  which  obtains  in  alveolar  air — namely,  about  95-100 
mm.  Hg;  and  to  obtain  the  rate  of  reduction  pure  N,  or  H2  gas  is  bub- 
bled through. 

The  rates  of  reduction  or  of  oxidation  as  thus  determined  are  then 
plotted   in   curves   constructed   with   the   percentage   saturation   of  the 


2P 22 90 loo  Oxidation 


17-5°  C.  no  CO, 


Reduction 


00 

80 

60 

B 

20 

Oxidation 


37-5°  C.  no  C02 


Reduction 


\ 

80 

\ 

X" 

^•^ 

\ 

/ 

\ 

f 

Y 

c 

40 

A 

/ 

20 

/ 

/ 

0 

/ 

Oxidation 


375°  C. 


+  40  mm.  pressure 
ofC02 


Reduction 

Fig.    141. — Curves   showing   relative   rates   of  oxidation   and   reduction   of  blood   as  influenced   by 
temperature  and  tension  of  CO2. 
Ordinates — Percentage   saturation. 
Abscissae. — Time    in    minutes. 
Reducing  gas,  hydrogen. 
Oxidizing  gas,   oxygen. 

A,  temperature    17.5°    C,    with    no    CO2. 

B,  temperature   37.5°    C,   with   no   CO2. 

C,  temperature   37.5°    C,   but  the   02   and   H   contained   40   mm.      Hg  pressure  of  C02.      (From 
Toseph   Barcroft.) 


388  THE   RESPIRATION 

hemoglobin  on  the  ordinates  and  the  time  in  minutes  along  the  abscissa? 
(Fig.  141).  Even  if  we  use  blood  in  this  experiment  and  therefore  make 
certain  that  the  hemoglobin  is  acting  in  the  presence  of  the  proper  pro- 
portion of  salts,  we  shall  find,  as  Fig.  A  shows,  that  at  room  temperature 
the  rate  of  oxidation  is  very  much  greater  than  the  rate  of  reduction. 
If  now  we  repeat  the  observation  at  a  temperature  of  37°  C,  the  two 
curves  come  more  nearly  to  correspond,  but  still  the  rate  of  reduction  is 
slower  than  that  of  oxidation.  If  in  a  third  experiment,  besides  having 
proper  temperature  and  chemical  conditions,  we  produce  the  oxidation 
and  reduction  in  the  presence  of  a  partial  pressure  of  C02  of  40  mm., 
which  corresponds  to  that  of  the  arterial  blood,  we  shall  find  that  oxida- 
tion becomes  a  little  slower,  whereas  reduction  is  further  quickened. 
Indeed  the  two  curves,  as  seen  in  C  in  the  figure,  come  practically  to 
correspond,  indicating  that  the  environmental  conditions  under  which 
hemoglobin  combines  and  gives  off  02  in  the  blood  are  exactly  adjusted. 

One  word  more  with  regard  to  the  influence  of  CH.  Its  effect  in  flat- 
tening out  the  curve,  especially  at  the  lower  partial  pressures  of  02, 
indicates  that  when  a  high  CH  is  present,  the  blood  will  very  readily  part 
with  its  02  supply.  Now,  the  most  significant  application  of  this  fact 
is  that  high  concentrations  of  11  ion  will  occur  just  exactly  where  it 
will  be  of  benefit — namely,  in  the  capillaries  (because  of  the  C02  and 
lactic  acid  produced  by  the  tissues).  Some  doubt  has,  however,  recently 
been  thrown  on  the  importance  of  this  factor. 

Since,  as  we  have  seen,  hemoglobin  absorbs  02  according  to  chemical 
laws,  it  will  naturally  be  asked  not  only  why  the  dissociation  curve  flat- 
tens out  while  yet  maintaining  the  shape  of  a  right-angled  hyperbola, 
as  by  the  action  of  acids  or  an  increase  in  temperature,  but  also  why  it 
should  change  its  shape  when  salts  are  also  present.  The  explanation 
offered  by  Barcroft  and  his  pupils  is  that  the  changes  depend  on  the 
fact  that  hemoglobin  being  a  colloidal  substance,  its  molecules  undergo 
processes  of  aggregation  under  the  conditions  referred  to  above,  and 
therefore  cause  the  reaction  to  become  of  a  different  type  from  that 
represented  by  the  equation  Hb02  <=*  Hb  +  02.  As  has  been  pointed  out 
by  Bayliss,  although  such  an  explanation  might  suffice  to  explain  the 
flattening  out  of  the  curve,  it  fails  to  explain  the  change  in  its  shape ; 
for,  according  to  the  laws  of  mass  action,  such  a  change  could  occur 
only  if  molecules  of  a  different  type  came  to  take  part  in  the  reaction. 

Dissociation  Constant. — Notwithstanding  these  criticisms,  it  is  of  con- 
siderable practical  importance  to  know  that  an  equation  exists  from 
which  the  entire  dissociation  curve  can  be  plotted  by  making  only  one 
determination  of  the  relative  amounts  of  oxy-  and  reduced  hemoglobin 
at  a  particular  tension  or  partial  pressure  of  oxygen.    This  equation  is  as 


RESPIRATION    BEYOND   THE    LUNGS  389 

y  K\" 

follows:  ~in  *==■  -= — 7= — ,  where  y  equals  llic   percentage  saturation  of 
100  l  +  kxn  * 

hemoglobin  with  02,  x  the  02  tension,  and  K  and  n  are  constants,  K 
being  the  equilibrium  constant  and  n  the  average  number  of  molecules 
of  hemoglobin  supposed  to  exist  in  each  aggregate. 

When  this  equation  is  applied  to  human  blood,  the  value  of  n  remains 
unchanged  and  is  given  as  2.5,  so  that  by  transposition  we  are  enabled 

y 

to  find  the  value  of  K  as  follows:  K  =^— — — .     If  we  find  the  value 

xn(lOO-y) 

of  K  by  measuring  the  relative  saturation  of  the  blood  with  02  at  one  pres- 
sure of  this  gas,  then  by  changing  the  value  of  x  to  correspond  to  other 
02  pressures,  we  can  find  all  positions  of  the  curve  for  a  given  sample  of 
blood. 

An  important  practical  application  of  this  method  is  found  in  the 
determination  of  the  CH  of  blood,  for,  as  we  have  seen,  the  dissociation 
curve  becomes  lowered  in  proportion  to  the  concentration  of  hydrogen 
ions.  The  acidity  of  a  sample  of  blood  can  therefore  be  found  by  com- 
parison of  its  dissociation  curve,  as  plotted  from  the  values  found  for 
K,  with  that  of  normal  blood  to  which  known  quantities  of  acid  have 
been  added.  When  the  curves  correspond,  the  bloods  must  contain  the 
same  amounts  of  acid,  other  things  being  equal.  In  brief,  then,  the  re- 
action of  the  blood  is  proportional  to  the  valve  of  K.  "When  this  is  low, 
it  indicates  that  the  blood  is  taking  up  an  abnormally  low  percentage 
of  its  possible  load  of  02  at  a  given  pressure  of  02,  and  that  the  acidity 
is  greater  than  normal;  when  K  is  high,  for  the  same  reason  the  acidity 
must  be  low. 

In  determining  K  for  the  blood  as  it  exists  in  the  body,  it  is  necessary 
that  it  should  be  subjected  to  the  same  tension  of  C02  as  obtains  in  the 
blood  vessels.  K  will  then  be  proportional  to  the  CH  of  the  living  blood. 
This  condition  would  be  impossible  to  fulfil  in  drawn  samples  were  it 
not  for  the  fact  that  we  can  place  in  the  tonometer  an  atmosphere  con- 
taining the  same  partial  pressure  of  C02  as  is  found  in  the  alveolar  air. 
Since  this  value  varies  in  different  individuals,  it  must  be  separately 
ascertained  in  each  case  (sec  page  344).  As  determined  with  these 
modifications,  K  has  been  found  to  vary  in  healthy  men  between 
0.000212  and  0.000363  (ten  individuals).  When  acid  substances  appear 
in  the  blood,  as  in  acidosis,  K  becomes  extremely  low;  thus,  in  one  case 
suffering  from  acidosis  with  dyspnea,  it  was  found  a  few  hours  before 
death  to  be  only  from  0.000082  to  0.00011.  Similarly  K  becomes  low 
in  the  acidosis  associated  with  mountain  sickness,  and  it  is  said  to  be 
raised  after  taking  food  that  is  rich  in  alkali.* 


,  it  is  said  to 


*When  K  is  found  to  be  normal,  the  blood  is  said  to  be  mesectic;  where   K  is  low,  it  is  s; 
be  myonectic;  and  when  K  is  high  and  the  acidity  is  therefore  small,  it  is  said  to  be  plconectic. 


CHAPTER  XLV 
RESPIRATION  BEYOND  THE  LUNGS— Cont'd 

THE  MEANS  BY  WHICH  THE  BLOOD  CARRIES  THE  GASES 

In  the  foregoing  account  of  the  physiology  of  the  blood  gases,  empha- 
sis is  placed  on  the  tension  under  which  the  gases  exist  rather  than  on 
the  total  amount  of  each  gas  present  in  the  blood.  This  has  been  done 
because  the  exchange  of  gases  between  alveolar  air  and  blood  and  be- 
tween blood  and  tissues  proceeds  according  to  the  laws  of  gas  diffusion, 
which  are  of  course  dependent  upon  differences  in  gas  pressure  or 
tension. 

Something  must  now  be  said  regarding  the  amount  of  the  gases.  This 
may  be  measured  either  by  physical  or  by  chemical  methods.  In  the 
former,  a  measured  quantity  of  blood  is  received  into  an  evacuated  glass 
vessel,  which  is  then  attached  to  a  mercury  pump,  by  which  the  gases 
are  sucked  out  of  the  blood  and  transferred,  by  suitable  manipulations 
of  stopcocks,  to  a  graduated  tube,  in  which  they  are  then  analyzed  by 
chemical  means.  The  principle  of  the  chemical  method  has  already  been 
described  in  connection  with  the  measurement  of  oxygen  in  hemoglobin 
solutions  (see  page  382).  A  measured  quantity  of  blood,  kept  free  from 
contact  with  the  air,  is  transferred  under  some  weak  ammonia  solution 
to  one  of  the  blood-gas  bottles  of  the  blood-gas  differential  manometer, 
and  a  few  drops  of  a  saturated  solution  of  potassium  ferricyanide  is 
placed  in  the  pocket  of  the  bottle.  After  the  blood  has  been  laked  and 
temperature  conditions  adjusted,  the  ferricyanide  is  mixed  with  the 
blood  solution,  thus  causing  the  02  to  be  quantitatively  displaced.  From 
the  increased  pressure  produced  in  the  manometer  the  amount  of  0,  can 
readily  be  computed.  To  determine  the  C02  of  the  blood,  the  bottle  is 
now  removed  from  the  manometer  and  a  few  drops  of  a  saturated  solu- 
tion of  tartaric  acid  placed  in  the  pocket.  When  this  is  mixed  with  the 
deoxygenated  blood  mixture,  after  the  usual  adjustment  for  tempera- 
ture, the  pressure  caused  by  the  evolved  C02  is  recorded  and  the  amount 
present  calculated. 

The  results  of  the  analysis  are  expressed  as  the  number  of  cubic  centi- 
meters of  gas  present  in  100  c.c.  of  blood — the  volume  percentage,  as  it 
is  called.     The  following  are  approximate  percentage  values: 

390 


RESPIRATION    BEYOND   THE    LUNG8  :!!»1 


OXYGEN 

CARBON   DIOXIDE 

TOTAL  GAS 

Venous  blood 

12 

48 

60 

Arterial   Mood 

20 

40 

60 

The  estimation  of  the  amounts  of  the  gases,  although  of  little  value 
in  connection  with  the  physiology  of  gas  exchange,  is  very  important  in 
supplying  information  regarding  the  respiratory  activities  of  the  various 
organs  and  tissues.  Just  as  we  determine  the  total  respiratory  exchan<_r<' 
of  an  animal  by  measuring  the  differences  in  0,  and  C02  in  inspired  and 
expired  air,  so  may  we  determine  the  degree  of  tissue  respiratory  ex- 
change by  analysis  of  the  gases  in  blood  removed  from  the  artery  and 
vein  of  the  tissue.  It  should  be  clearly  understood,  however,  that  it  is 
not  the  percentage  but  the  total  amount  of  the  gases  that  must  be  con- 
sidered, and  that  it  is  therefore  necessary  to  know  the  volumes  of  blood- 
flow  as  well  as  the  percentage  of  the  gases.  Something  will  be  said  later 
of  the  results  of  such  investigations  (see  page  393)'. 

At  present  we  are  concerned  with  the  manner  in  which  gases  are 
carried  in  the  blood.  The  02,  as  we  have  seen,  is  carried  by  the  hemo- 
globin, some  being  also  in  a  state  of  simple  solution  in  the  plasma.  The 
C02,  which  it  will  be  noted  is  present  even  in  arterial  blood  in  con- 
siderably greater  amount  than  the  02,  is  partly  combined  with  alkali  to 
form  bicarbonates.  The  alkali  available  for  this  purpose  varies  from 
time  to  time  according  to  the  amount  of  other  acid  substances  present. 
Since  these  are  stronger  acids  than  carbonic,  any  increase  in  their 
amount  (acidosis)  causes  displacement  of  some  of  the  C02,  thus  bring- 
ing about,  as  we  have  seen,  a  relative  increase  in  free  CO,  in  the  blood 
and  therefore  raising  the  CH. 

"What  particularly  interests  us  here  is  the  agency  by  which  the  com- 
bined C02  is  carried  in  the  blood.  If  blood  is  exposed  to  a  full  atmos- 
phere of  CO,,  it  will  take  up  as  much  as  150  per  cent  of  the  gas — that 
is,  between  two  and  three  times  the  amount  ordinarily  present  in  it. 
It  has  therefore  a  great  reserve  capacity  for  C02.  A  greater  propor- 
tion of  the  C02  is  carried  in  the  plasma  than  in  the  corpuscles;  but  if 
plasma  (or  serum)  is  exposed  in  a  vacuum,  all  of  the  C02  present  in  it 
will  not  be  evolved.  When  blood  itself  is  similarly  exposed,  on  the 
other  hand,  all  the  CO,  is  given  off.  To  liberate  all  of  the  CO,  from 
plasma  in  vacno,  some  acid  must  be  added,  from  which  it  has  been  in- 
ferred that  blood  corpuscles  act  like  weak  acids.  It  is  commonly  stated 
that  hemoglobin  or  some  constituent  of  blood  is  capable  of  freeing  CO, 
from  solutions  of  sodium  carbonate,  but  the  recent  work  of  Buckmaster '■'■- 
shows  that  this  is  not  the  case.  The  decomposing  power  of  blood  is 
caused  by  the  development  of  acidity  in  the  shed  blood  and  any  similar 
power   that    the    corpuscles   may   exhibit    is    due   to    a   discharge    from 


392 


THE   RESPIRATION 


them  into  the  plasma  of  acid  radicles.  At  least  it  has  been  found  that 
the  alkalinity  of  the  plasma  increases  when  C02  is  bubbled  through 
blood,  this  increase  in  alkalinity  being  interpreted  as  the  result  of  the 
migration  of  acid  radicles  into  the  corpuscles.  This  would  lead  us  to 
expect  that  under  the  opposite  conditions  (i.  e.,  in  vacuo)  acids  would 
leave  the  corpuscles. 

Proteins  are  amphoteric  substances — that  is,  they  combine  with  acids 
or  alkalies — which  would  lead  us  to  expect  that  they  would  be  capable 
of  absorbing  some  C02.     That  this  is  the  case,  particularly  for  hemo- 


o  eo 


.r 


55 


50 


45" 


:         ^ 

*,'    ^ 

-    t£-        *    - 

/    J          y 

r                          *' ' 

' 

,' 

A 

,<' 

_.- 

/ 

,' 

) 

■' 

/ 

40 


30         40  50  60  70  80         90 

'S'lt&ruAjL     o|     CO,    vrv     rrvm.    3£a. 

Fig.    142. — Curve   of  CO«   tension   in   blood.      For   description,   see   text.      (From   Christiansen,    Doug- 
las and   Haldane.) 

globin,  has  been  shown  by  comparing  the  C02-combining  powers  of  water 
and  a  solution  of  pure  hemoglobin. 

Attempts  have  been  made  to  determine  the  relative  amounts  of  CO, 
carried  by  these  various  agencies  in  the  blood.  The  following  is  an  ex- 
ample of  such  a  table: 


In  simple  solution  in  plasma  and  corpuscles  1.9  c.c. 

a  v        t       1        4.       1  o  in  corpuscles  6.S  1  (t 

As  sodium  bicarbonate      t  a  ■        1  -10  n   1     -18-8 

J  /3  in  plasma  12.0  J 

19.3    " 


In  combination  with  hemoglobin 

In  combination  with  proteins  of  plasma 


(.0 

11.8 


40.0 


(Loewy.) 


KKS1MKATI0N    BEYOND   THE   LUNGS  393 

The  power  of  blood  to  absorb  CO.,  at  various  tensions  of  this  gas,  as 
determined  in  the  same  way  as  !'<>r  02  (see  page  380),  lias  shown  thai 
saturation  of  the  hemoglobin  with  02  distinctly  diminishes  the  C02- 
earrying  power  of  the  blood.    This  is  shown  in!  the  accompanying  curves 

The  various  tensions  of  C02  are  given  along  the  abscissae  and  the 
volume  per  cents  of  C02  taken  up  by  the  blood  on  the  ordinates.  The 
upper  curve  is  drawn  from  results  obtained  when  the  blood  was  shaken 
with  C02  in  the  presence  of  hydrogen,  and  the  lower,  when  in  the 
presence  of  air.  (The  dotted  curve  may  be  disregarded.)  The  line  AB 
drawn  between  the  two  curves  represents  the  absorption  of  CO,  by  the 
blood  within  the  body.  At  a  tension  of  40  mm.  C02 — that  present  in 
alveolar  air  (see  page  356) — A  stands  in  arterial  blood  at  about  52  vols, 
per  cent;  and  at  a  pressure  of  62  mm. — possibly  present  in  the  tissues — 
B  stands  in  venous  blood  at  about  67  vols,  per  cent.  The  C02-eontaining 
power  would  be  7  per  cent  lower  (i.  e.,  60  vols,  per  cent)  in  blood  saturated 
with  02  at  the  latter  pressure.  The  oxygenation  of  blood  in  the  lungs, 
therefore,  helps  to  drive  out  the  C02;  and  conversely,  its  deoxygenation 
in  the  tissues  enhances  its  power  of  absorbing  this  gas. 

Having  shown  how  the  blood  transports  its  charge  of  02  from  the 
lungs  to  the  tissues,  we  may  now  proceed  to  study  the  call  for  02  by 
the  tissues,  and  in  this  connection  we  have  to  consider  (1)  the  amount 
of  02  which  they  require  under  varying  conditions  of  rest  and  activity, 
and  (2)  the  mechanisms  by  which  their  varying  demands  are  met. 

THE  OXYGEN  REQUIREMENT  OF  THE  TISSUES 

In  order  to  ascertain  the  average  02  requirement  of  the  different  tis- 
sues of  the  body,  it  is  necessary  to  adopt  as  a  standard  of  measurement 
the  amount  of  02  in  c.c.  absorbed  per  gram  of  tissue  per  minute.  To  ob- 
tain it  we  must  know:  (1)  the  weight  of  the  particular  organ  or  tissue 
under  investigation;  (2)  the  bloodflow  through  the  vessels  of  the  organ 
in  c.c.  per  minute;  and  (3)  the  different  percentages  of  02  in  the  arterial 
and  venous  blood  of  the  tissue.  It  Avould  be  beyond  the  scope  of  this 
book  to  review  in  any  detail  the  many  experimental  investigations  which 
have  been  undertaken  in  this  connection.  A  few  of  the  most  recent 
and  important  results  are  given  in  the  accompanying  table  from  Halli- 
burton 's  Physiology : 

In  the  order  of  their  oxygen  requirements,  or  the  coefficient  of  oxida- 
tion, as  it  is  called,  the  tissues  may  be  divided  into  four  groups ;  glandular, 
muscular,  connective,  and  nervous.  The  nervous  tissues  should  possibly 
stand  above  the  connective,  but  very  little  is  known  regarding  their 
oxygen  consumption,  although  it  appears  that  this  is  quite  low  (Hill  and 


394 


THE    RESPIRATION 


ORGAN 

CONDITION    OF    REST 

OXYGEN  USED 

PER    MINUTE 

PER  GRAM 

OF  ORGAN 

CONDITION   OF  ACTIVITY 

OXYGEN 

USED    PER 

MINUTE 

PER    GRAM 
OF    ORGAN 

Voluntary 

Nerves  cut.    Tone 

0.003    C.C 

Tone  existing  in  rest 

o.ooe 

i  cc 

muscle 

absent 

Gentle  contraction 

0.02C 

1  cc 

Active  contraction 

0.080 

C.C 

Unstriped 
muscle 

Eesting 

0.004  cc. 

Contracting 

0.007 

'  cc 

Heart 

Very  slow  and 

0.007  cc. 

Normal  contractions 

0.05 

C.C 

feeble  contractions 

Very  active 

0.08 

C.C. 

Submaxillary 

Nerves  cut 

0.03  cc. 

Chorda  stimulations 

0.10 

cc 

gland 

Pancreas 

Not  secreting 

0.03  cc 

Secretion  after  injec- 
tion of  secretin 

0.10 

C.C. 

Kidney 

Scanty  secretion 

0.03  cc 

After  injection  of 
diuretic 

0.10 

C.C. 

Intestines 

Xot  absorbing 

0.02  cc 

Absorbing  peptone 

0.03 

cc 

Liver 

In  fasting  animal 

n.oi  to 

In  fed  animals 

0.03 

to 

0.02  cc 

0.05 

C.C. 

Suprarenal 

Normal 

0.045  cc 

gland 

Xabarro).  It  is  of  course*  necessary  in  making  these  comparisons  to 
secure  the  coefficient  of  oxidation  both  when  the  tissue  is  at  rest  and 
when  it  is  thrown  into  varying  degrees  of  activity.  Special  attention 
has  been  devoted  to  the  requirements  of  skeletal  muscle,  heart  muscle 
and  the  salivary  glands. 

Skeletal  Muscle. — In  observations  on  skeletal  muscle,  Verzar  (cf.  27) 
isolated  the  gastrocnemius  muscle  of  the  cat,  and  without  disturbing  its 
blood  supply  collected  samples  of  blood  by  introducing  a  1  cc.  pipette 
into  a  branch  of  the  saphenous  vein.  Activity  was  produced  by  throw- 
ing the  muscle  into  tetanus  by  the  application  of  an  electrical  stimulus 
to  the  sciatic  nerve.  During  its  contraction  the  muscle  lifted  a  weight, 
so  that  it  did  about  70  gram-centimeters  of  work  at  the  beginning  of 
each  period  of  tetanus.  The  velocity  of  bloodflow  was  determined  by 
the  rate  at  which  the  blood  flowed  along  the  pipette,  and  the  02  consump- 
tion, by  the  difference  in  percentage  of  02  in  the  venous  and  the  arterial 
blood.  These  measurements  were  made:  (1)  before  contraction,  (2)  dur- 
ing contraction,  and  (3)  after  contraction.  It  was  found  that  during  the 
tetanus  the  02  consumption  in  some  eases  was  greater  than  during  rest, 
while  in  others  it  was  actually  less,,  but  in  every  instance  a  great  increase 
in  02  consumption  followed  the  tetanus — that  is,  the  call  for  02  continues 
for  some  time  after  the  actual  work  has  been  performed.     This  result 


RESPIRATION    BEYOND    THE    LUNGS  395 

shows  that  the  contraction  is  not  dependent  upon  oxidation,  but  that 
the  oxidation  occurs  after  the  contraction  is  over.  The  mechanism  involved 
in  muscular  contraction  can  not  therefore  be  analogous  "with  that  by 
which  energy  is  liberated  in  a  steam  engine  by  the  oxidation  of  the  coal. 
The  mechanism  must  rather  be  like  that  of  a  spring,  which  becomes  un- 
wound during  the  muscular  contraction  and  requires  02  for  its  rewinding. 

Interesting  results  corroborative  of  these  conclusions  have  been  se- 
cured by  observations  on  the  heat  production  of  isolated  muscles.  It 
was  found  that  heat  production  occurred  after  a  single  shock  to  the 
muscles,  not  only  during  the  contraction,  but  for  a  considerable  period 
after  it,  provided  02  was  present.  In  the  absence  of  02  this  recovery 
was  either  greatly  delayed  or  entirely  abolished.  Such  results  favor 
the  view  that  02  is  used  largely  in  the  processes  whereby  the  muscles, 
"like  an  engine  charging  an  accumulator,  synthesize  substances  con- 
taining a  considerable  amount  of  potential  energy,  which  again,  like  the 
accumulator,  it  discharges  when  appropriate  stimuli  are  applied" — (L. 
V.  Hill,  cf.  27).  One  immediately  thinks  of  lactic  acid  in  connection 
with  these  interesting  results,  for,  as  has  already  been  stated,  Hopkins 
and  Fletcher29  have  shown  that  this  acid  is  produced  in  the  absence  of 
02  in  excised  frog  muscles,  but  when  02  is  present,  it  is  either  not  pro- 
duced or,  if  so,  quickly  disappears. 

Heart  Muscle. — Another  muscle  that  has  been  thoroughly  investigated 
in  this  connection  is  that  of  the  heart.  The  gaseous  exchange  has  been 
studied  both  on  isolated  heart  preparations  and  by  examining  the  ex- 
change in  the  lungs  of  a  combined  lung  and  heart  preparation.  The 
most  important  investigations  by  the  first  of  these  methods  are  those  of 
Rohde  (cf.  27),  who  arrived  at  the  very  important  conclusion  that  the 
0,  taken  in  by  the  heart  muscle  varies  directly  with  the  maximal  ten- 
sion set  up  in  the  heart  by  the  contraction.  This  tension  was  measured 
by  placing  a  rubber  bag  in  the  ventricle  and  distending  it  with  water  at 
a  known  pressure.  By  altering  the  initial  pressure  and  by  observing  the 
pulse  rate,  it  was  found  that  the  02  used  by  the  heart  depends  on  the 
product  of  the  pulse  frequency  and  the  maximal  increase  in  pressure 
produced  by  each  cardiac  contraction;  or,  in  the  form  of  an  equation: 

Q  •      , 

. =  a  constant  quantitv;  where  Q  is  the  oxv^en  used,  T  the  maximal 

NT 

increase  of  pressure  at  each  beat,  and  N  the  frequency  of  the  pulse. 

It  should  be  pointed  out,  however,  that  constancy  in  the  product  of 
the  above  equation  does  not  hold  under  abnormal  conditions  of  the  heart- 
beat. For  example,  when  the  pressure  in  the  heart  is  very  high,  the 
amount  of  02  required  begins  to  go  up  out  of  proportion,  indicating  that 


396  THE   RESPIRATION 

the  heart  is  becoming  overtaxed — that  it  is  losing  its  efficiency.  The 
same  result  occurs  when  the  heart  is  dying,  and  when  depressing  drugs 
are  used,  such  as  chloral  hydrate,  potassium  cyanide,  veratrine,  etc. 
Some  other  drugs,  however,  such  as  epinephrine,  do  not  cause  altera- 
tion in  the  ratio,  nor  does  vagus  stimulation.  Of  course  when  the  vagus 
is  stimulated,  the  02  consumption  in  a  given  period  decreases  because 
the  heartbeats  are  slowed ;  but  the  absorption  of  02  is  not  increased  rela- 
tively to  the  slowing  of  the  heart. 

Glands. — Most  work  has  naturally  been  done  on  the  most  accessible 
gland — the  submaxillary.  By  stimulating  the  secretory  nerve  of  this 
gland  (the  chorda  tympani)  in  the  dog,  it  has  been  found  that,  whereas 
the  more  abundant  secretion  lasts  only  so  long  as  the  stimulus  is  ap- 
plied to  the  nerve,  the  02  consumption  is  increased  to  several  times  that 
of  rest,  and  remains  increased  for  a  considerable  period  after  the  stimulus 
has  been  removed.  Accompanying  the  increased  functional  activity  in 
such  structures  as  muscles,  there  is  a  very  marked  increase  in  bloodflow 
due  to  vasodilatation,  which,  in  part  at  least,  is  dependent  upon  the 
secretion  into  the  blood  of  some  substances  resulting  from  the  glandular 
activities,  and  is  not  entirely  due  to  the  action  of  vasodilator  nerve  fibers. 

Similar  results  have  been  obtained  in  the  case  of  the  pancreas  when 
excited  to  secrete  by  the  injection  of  secretin  (see  page  425).  Under 
such  conditions,  the  oxygen  consumption  has  been  observed  to  increase 
about  fourfold  and  to  be  accompanied  by  a  dilatation  of  the  gland. 

The  work  on  the  kidney  has  been  especially  interesting,  because  it 
has  been  found  that  increased  activity,  which  of  course  is  measured  by 
the  rate  of  urine  excretion,  is  not  always  accompanied  by  increased 
consumption  of  oxygen.  When  diuresis  is  produced  by  injecting  Eing- 
er's  solution  into  the  circulation,  a  great  increase  in  urine  outflow  may 
occur  without  any  change  in  oxygen  consumption ;  whereas,  on  the  other 
hand,  when  a  diuretic  such  as  sodium  sulphate  or  caffeine  is  used,  the 
oxygen  consumption  increases   enormously. 

Regarding  the  other  tissues  and  organs,  the  02  consumption  of  the 
lungs  and  brain  appears  to  be  small.  It  is  a  very  significant  fact,  how- 
ever, that  the  higher  cerebral  centers  are  extremely  sensitive  to  depri- 
vation of  02. 

The  Blood. — In  the  blood  itself,  a  certain  amount  of  oxidation  goes 
on  because  of  the  presence  of  leucocytes.  This  oxidation  becomes  con- 
siderable in  the  blood  of  animals  rendered  anemic  by  the  injection  of 
phenyl  hydrazin.  A  thorough  investigation  of  the  cause  of  this  greater 
oxidation  has  shown  it  to  be  owing,  not  to  an  increase  in  nucleated 
corpuscles,  but  to  the  presence   of  the  young  unnucleated  red  blood 


RESPIRATION    BEYOND   THE    LI  \<;s  397 

corpuscles,  which  appear  in  Large  aumbers  in  the  I)1<><»<1  under  these  con- 
ditions. A  similar  increase  in  blood  oxidation  occurs  during  posthemor- 
rhagic anemia,  the  rate  of  oxidation  running  parallel  with  the  rate  of 
regeneration  of  the  nn\  corpuscles. 

The  Mechanism  by  Which  the  Demands  of  the  Tissues  for 
Oxygen  Are  Met 

There  are  two  possible  methods  by  which  this  may  be  brought  about: 

(1)  by  a  change  in  the  CH  or  the  saline  constituents  or  the  temperature  of 
the  plasma,  so  that  the  hemoglobin  more  readily  delivers  up  its  load 
of  02;  and  (2)  by  an  increase  in  the  mass  movement  of  blood  through 
the  vessels  of  the  acting  tissue. 

Kegarding  the  first  of  these  possibilities,  there  is  no  doubt  that  acids 
are  produced  during  metabolism  of  acting  tissues.  As  we  have  seen, 
when  muscles  contract  in  the  presence  of  an  abundance  of  02,  C02  is 
produced  in  large  amounts,  and  when  they  contract  in  a  deficiency  of  02, 
sarcolactic  acid.  In  the  submaxillary  gland,  too,  it  has  been  possible  to 
show  that  the  Ch  of  the  venous  blood,  as  measured  by  the  value  of  K  of 
the  dissociation  curve  of  hemoglobin,  becomes  distinctly  increased  dur- 
ing glandular  activity.  That  this  increase  in  CH  will  dislodge  02  we  have 
already  seen  (page  386).  As  to  the  possible  influence  of  local  changes 
in  temperature  and  in  saline  constituents  of  the  plasma,  nothing  can  at 
present  be  said. 

Regarding  the  second  possibility,  vasodilatation  may  be  dependent 
either  upon  the  action  on  the  blood  vessels  of  nerve  impulses  coming 
along  vasomotor  nerves,  or  upon  the  production  by  the  active  tissue  of 
vasodilating  or  depressor  substances  (see  page  243).  Much  evidence 
has  been  accumulating  in  recent  years  which  tends  to  show  that  such 
depressor  substances  are  produced,  and  they  may  be  either  (1)  acids,  or 

(2)  organic  bases  of  a  similar  nature  to  /3-imidazolylethylamine  (hista- 
mine). This  latter  substance  is  of  considerable  physiologic  interest  be- 
cause of  its  close  relationship  to  one  of  the  main  amino  acids  of  the 
protein  molecule — namely,  histidine  (see  page  604).  Its  effect  in  pro- 
ducing vasodilatation  is  extraordinary.  Thus,  half  a  milligram  of  the 
drug  injected  intravenously  into  a  monkey  will  lower  the  mean  arterial 
pressure  by  fifty  per  cent. 

But  before  such  an  hypothesis  can  be  entertained,  it  is  necessary  to 
show  that,  independently  of  nerve  impulses,  the  blood  vessels  of  an  acting 
organ  may  dilate.  The  best  evidence  has  been  secured  by  studying  the 
effects  of  stimulating  with  epinephrine  the  cervical  sympathetic  nerve  to 
the  submaxillary  gland  of  a  cat.     The  gland  cells  become  more  active, 


398  THE   RESPIRATION 

and  dilatation  of  the  artery  occurs,  although  on  blood  vessels  alone 
epinephrine  in  similar  dosage  produces  constriction.  Of  course  in  show- 
ing that  local  chemical  products  of  activity  serve  as  the  excitant  of  local 
dilatation,  we  do  not  mean  to  imply  that  the  vasodilator  fibers  going  to 
the  blood  vessels  are  of  no  use.  Indeed  v\-e  know  that  such  fibers  do  be- 
come active  in  the  case  of  a  salivary  gland  whose  cells  have  been  para- 
lyzed by  atropine,  but  it  is  a  significant  fact  that  this  dilatation  is  of  rela- 
tively short  duration,  whereas  that  produced  by  glandular  activity  lasts 
for  some  time.  The  suggestion  seems  therefore  not  out  of  place  that  un- 
der normal  conditions  the  initial  dilatation  of  an  acting  gland  may  be 
brought  about  through  nervous  stimuli,  but  the  later  dilatation  is  main- 
tained by  metabolic  products. 


CHAPTER  XLVI 

THE  PHYSIOLOGY  OF  BREATHING  IN  COMPRESSED  AIR  AND 

IN  RAREFIED  AIR 

In  the  application  of  a  knowledge  of  the  phj-siology  of  respiration  to 
the  investigation  of  disease,  a  group  of  conditions  arises  in  which  con- 
siderable interference  with  physiologic  mechanisms  occurs,  not  as  a  result 
of  disease,  but  of  changes  in  the  atmospheric  environment.  The  regula- 
tion of  the  functions  of  respiration  depends  very  largely  on  changes  in 
the  physical  and  chemical  properties  of  the  alveolar  air,  so  that  it  is  to 
be  expected  that  similar  changes  in  the  atmosphere  will  have  a  marked 
influence  on  the  respiratory  activity  and  on  the  general  well-being  of 
the  animal. 

The  most  thoroughly  investigated  of  these  conditions  are. those  which 
develop  in  rarefied  and  compressed  air.  Either  condition  can  be. pro- 
duced experimentally  in  the  laboratory  by  the  use  of  air-tight  chambers 
(pneumatic  cabinets)  and  suitable  pumps,  although  most  of  the  im- 
portant work  on  the  effects  of  rarefied  air  has  been  conducted  at  high 
altitudes,  where  the  barometric  pressure  is  low. 

MOUNTAIN  SICKNESS 

This  condition  depends  primarily  on  disturbances  in  the  control  of  the 
respiratory  function,  and  it  is  on  account  of  the  useful  information  con- 
cerning the  nature  of  these  functions,  rather  than  because  of  the  so-called 
disease  itself,  that  so  much  attention  has  been  devoted  to  its  investiga- 
tion during  recent  years.  The  disturbances  produced  by  the  rarefied 
atmosphere  develop  rather  quickly,  but  after  some  time  they  gradually 
disappear,  indicating  that  the  organism  has  acclimated  itself — that  is, 
the  compensatory  mechanisms  have  come  into  play  to  bring  the  respira- 
tory control  back  to  normal.  When  animals  are  placed  in  pneumatic 
cabinets  from  which  some  of  the  air  is  pumped  out,  most  of  the  imme- 
diate symptoms  observed  in  mountain  sickness  occur,  but  it  is  usually 
impracticable  to  continue  the  observations  for  a  sufficient  length  of 
time  to  allow  the  compensating  mechanisms  to  develop. 

Because  of  their  great  value  in  revealing  the  nature  of  the  respiratory 
hormone,  many  of  the  results  of  the  recent  investigations  on  mountain 

399 


400  THE   RESPIRATION 

sickness  have  been  given  elsewhere  in  this  volume  (page  360),  where  the 
general  symptoms  are  also  described.  In  this  place  we  shall  consider 
very  briefly  some  of  the  more  general  aspects  of  the  condition,  and,  more 
particularly,  the  nature  of  the  adaptation  that  occurs.  All  of  the  symp- 
toms are  essentialy  dependent  upon  lack  of  oxygen.  Cyanosis  is  com- 
mon and  the  symptoms  are  much  the  same  as  those  of  coal-gas  poisoning. 
Not  only  does  this  deficiency  of  oxygen  cause  acid  substances  to  appear 
in  the  blood,  thus  raising  the  CH  and  stimulating  the  respiratory  center, 
but  it  allows  other  poisonous  materials  to  accumulate.  These  act  on  the 
various  nerve  centers,  producing  symptoms  which  vary  in  different  in- 
dividuals according  to  their  relative  susceptibilities.  In  some,  the  diges- 
tive centers  are  affected  and  nausea  and  vomiting  occur;  in  others,  the 
higher  cerebral  centers  are  affected,  causing  depression  and  general  men- 
tal apathy,  great  drowsiness,  muscular  weakness,  or  it  may  be  mental 
excitement  and  loss  of  self-control. 

The  susceptibility  of  different  individuals  also  varies  according  to  the 
amount  of  previous  experience  in  mountaineering  and  the  type  of  breath- 
ing. Much  of  the  value  of  previous  experience  and  training  depends  on 
the  ability  to  perform  muscular  effort  economically;  to  adjust  the  effort 
to  the  available  oxygen  supply  without  permitting  unoxidized  harmful 
products  to  accumulate  in  the  body.  It  often  happens  that  no  symptoms 
appear  so  long  as  the  person  is  at  rest,  but  immediately  do  so  whenever 
any  muscular  effort  demands  a  much  more  abundant  oxygen  supply. 

The  type  of  breathing  that  best  withstands  the  rarefied  air  is  slow  and 
deep,  rather  than  rapid  and  shallow.  The  reason  for  this  is  of  course 
that  much  more  of  the  outside  oxygen  gets  into  the  alveoli  in  the  former 
case  than  in  the  latter,  the  dead  space  being  practically  constant.  The 
following  figures  taken  from  observations  on  three  different  individuals 
will  illustrate  the  importance  of  this  factor. 


C.C.  PEE 

NO.  OP  RES- 

HEIGHT IN  METERS 

RESPIRATION 

PIRATIONS 

AT  WHICH  SYMP- 

PER MINUTE 

TOMS  OCCURRED 

Subject  1 

270 

20 

3300 

"        2 

440 

14 

6000 

"       3 

700 

8 

6500 

(From  Halliburton.) 

After  living  for  some  time  in  the  rarefied  air  and  quite  independently 
of  training  in  the  efficient  performance  of  muscular  work,  adaptation 
occurs,  so  that  the  symptoms  pass  off.  The  essential  feature  of  this  adap- 
tation is  increased  absorption  of  02  into  the  blood.  Three  mechanisms 
have  been  described  as  responsible  for  this  effect:  (1)  increase  in  the  ten- 
sion of  02  in  the  alveolar  air;  (2)  assumption  by  the  pulmonary  epithelium 


lSKi:.\THIN(i    IN    COMI'KKXXKI)    AND    IN     RABBETED    AIR  101 

of  the  power  of  secreting  02  into  the  blood;  (3)  increase  in  the  erythrocytes 
ami  hemoglobin  of  the  blood.  The  increased  alveolar  0a  tension  is  a  result 
of  the  more  rapid  breathing  broughl  about  by  the  increased  CH  of  the 
blood.  If  no  adaptation  occurred,  the  02  tension  at  10,000  feet  would  be 
59  mm.  and  at  15,000  feet,  33.8  mm.  Actual  observations  on  men,  how- 
ex  er,  gave  at  10,000  feet  a  tension  of  65  mm.  and  at  15,000  feet,  52  mm. 

The  evidence  for  an  increased  secretory  activity  of  the  pulmonary 
epithelium  depends  on  observations  made  by  Haldane  and  his  cowork- 
ers,33 who  found  that  blood  collected  from  the  finger  of  a  man  living  on 
a  high  mountain  is  brightly  arterial,  whereas  if  this  same  blood  is 
shaken  in  a  flask  with  alveolar  air  from  the  man  from  whom  it  was 
taken,  it  will  become  darkly  venous.  To  account  for  this  difference  it  is 
believed  that  the  pulmonary  epithelium  forces  O,  into  the  blood  contrary 
to  the  laws  of  diffusion. 

A  more  exact  proof  was  sought  for  by  comparing  the  relative  amounts 
of  02  and  CO  that  blood  would  take  up  (1)  when  exposed  outside  the 
body  and  (2)  while  in  the  blood  vessels.  Carbon  monoxide  has  a  very 
great  avidity  for  hemoglobin,  so  that  if  blood  is  shaken  in  a  flask  with 
air  containing  0.07  per  cent  of  this  gas,  colorimetric  measurement  will 
show  an  equal  mixture  of  oxy-  and  carboxy-hemoglobin.  Since  carbon 
monoxide  is  destroyed  with  extreme  slowness  in  the  body,  it  is  possible 
by  causing  a  man  to  breathe  a  mixture  of  it  in  air  to  determine,  in  a 
sample  of  drawn  "blood,  whether  as  much  carboxy-hemoglobin  has  been 
formed  as  in  vitro.  If  so,  the  02  tension  in  the  blood  must  equal  that  in 
the  alveoli;  if  less  carboxy-hemoglobin  should  be  formed,  it  would  indi- 
cate that  a  higher  tension  of  02  exists  in  the  blood.  This  latter  is  the  re- 
sult which  Haldane  states  he  has  secured.  In  one  experiment,  for  ex- 
ample, when  blood  was  shaken  outside  the  body  with  0.04  per  cent  C02, 
the  amount  of  carboxy-hemoglobin  formed  was  31  per  cent  of  the  whole 
hemoglobin.  When  the  same  mixture  was  inhaled  for  three  or  four  hours 
the  percentage  of  carboxy-hemoglobin  in  the  blood  rose  only  to  26  per 
cent,  which  would  correspond  to  an  O,  tension  of  25  per  cent  of  an  atmos- 
phere, whereas  even  at  sea  level  the  tension  of  02  in  the  alveolar 
air  can  not  be  above  15  per  cent  of  an  atmosphere. 

The  constant  low  tension  of  02  in  the  plasma  stimulates  the  red  blood 
corpuscles  and  the  percentage  of  hemoglobin  to  become  markedly  in- 
creased after  residence  for  some  time  in  high  altitudes.  At  first  this  is 
due  to  a  concentration  of  the  blood  by  a  diminution  in  plasma,  but  grad- 
ually the  blood-forming  organs  become  excited  and  an  actual  increase 
in  the  total  amount  of  hemoglobin  occurs.  In  the  light  of  these  facts  it 
is  interesting  to  compare  the  average  number  of  red  corpuscles  in  the 
blood  of  inhabitants  living  at  different  altitudes. 


4:02  THE    RESPIRATION 


Christiania 

Zurich 

Davos 

Arosa 

( Jordilleras 


HEIGHT  ABOVE  SEA 

RED  CORPUSCLES 

(meters) 

(PER  c.mm.  blood) 

0 

4,970,000 

412 

5,752,000 

15(50 

6,551,000 

1800 

7,000,000 

4392 

8,000,000 

(From  Starling.) 

COMPRESSED-AIR  SICKNESS;  CAISSON  DISEASE; 
DIVER'S  PALSY 

Divers  and  caisson  workers  are  susceptible  to  peculiar  symptoms. 
These  are  frequently  of  sufficient  severity  to  cause  death,  but  may  be  so 
mild  as  almost  to  escape  notice.  They  first  appear,  not  when  the  worker 
is  subjected  to  the  high  pressure,  but  after  he  has  come  back  to  atmos- 
pheric pressure.* 

While  in  the  compressed  air  the  worker  as  a  rule  suffers  no  discom- 
fort. A  stuffiness  may  be  felt  in  the  ears  and  temporary  giddiness;  the 
respiration  and  pulse  rate  may  become  slow  and  frequency  of  micturition 
may  be  noticed,  but  none  of  the  symptoms  of  disease  appear  until  after 
the  caissonier  or  diver  has  been  decompressed  (after  he  has  returned  to 
atmospheric  pressure),  the  exact  time  of  their  onset  being  either  imme- 
diately after  decompression  or  at  the  end  of  several  hours.  The  worker 
may  have  returned  home  and  spent  the  evening  feeling  perfectly  well 
until  he  went  to  bed,  when  symptoms  supervened  which  may  include  mus- 
cular and  joint  pains,  vertigo,  embarrassed  breathing,  subcutaneous  em- 
physema and  hemorrhages,  pains  in  the  ears  and  deafness,  vomiting, 
perhaps  hemoptysis  and  epigastric  pain.  These  symptoms  usually  pass 
off  after  some  hours  but  the  arthralgia  and  myalgia  sometimes  persist 
for  a  considerable  time. 

In  the  more  severe  cases  the  first  symptom  is  severe  pain  in  the  mus- 
cles and  joints,  quickly  followed  by  motor  paralysis,  so  that  the  patient 
falls  and  is  likely  to  become  unconscious.  The  pulse  is  almost  imper- 
ceptible, the  respiration  is  labored,  sometimes  even  asphyxial,  the  face 
cyanosed,  and  the  surface  of  the  body  cold.  Many  of  the  cases  are  fatal ; 
indeed,  death  may  be  almost  instantaneous.  Such  cases  are  common  in 
careless  diving  when  the  divers,  to  return  the  more  quickly,  screw  up  the 
outlet  valve  in  their  helmets  so  as  to  fill  their  suits  with  air,  which  car- 


*A  caisson  is  a  steel  or  wooden  chamber  sunk  in  water  and  prevented  from  filling  by  means  of 
compressed  air.  For  the  passage  of  the  workmen  and  of  material,  into  and  out  of  the  caisson;  the 
latter  is  connected  with  a  second  smaller  chamber  fitted  with  air-locks  and  decompressing  cocks.  A 
diver  works  in  a  waterproof  suit,  the  head  being  enclosed  in  a  copper  helmet  connected  by  hose  with 
air  pumps.  Every  10  meters  or  33  feet  of  water  corresponds  to  one  atmosphere  pressure  (15  pounds 
to  the  square  inch),  so  that  at  this  depth  the  total  air  pressure  in  a  caisson,  or  in  a  diver's  helmet, 
would  amount  to  30  pounds  to  the  square  inch,  that  is,  +  1   atmosphere. 


BREATHING    I  \    COMPRESSED    WD    I  \    RAREFIED    Ml:  403 

riea  them  to  the  Burface,  where  they  decompress  themselves  by  opening 
the  valve. 

Autopsies  of  persons  dead  of  caisson  disease  have  shown,  as  a  rule, 
intense  congestion  oi*  the  viscera,  hemorrhages  in  the  spinal  cord  and 
brain,  and  cccliymoses  on  the  pleura  and  pericardium.  In  some  cases 
interlobar  emphysema  of  the  lungs  and  laceration  of  the  spinal  cord  and 

brain  have  been  noted. 

The  Cause  of  the  Symptoms 

The  cause  for  the  symptoms  is  not,  as  was  at  one  time  supposed,  that 
the  pressure  drives  the  blood  from  the  peripheral  into  the  deep  regions 
of  the  body,  including  the  nerve  centers.  Such  a  process  is  impossible, 
because  the  fluids  of  the  body — and  all  tissues,  even  the  bones,  are  full 
of  fluid — are  incompressible.  Pressure  applied  to  any  part  of  the  body 
will  be  immediately  distributed  equally  to  every  other  part.  If  this  were 
not  so,  life  would  be  impossible  during  any  variation  of  atmospheric  pres- 
sure. It  is  now  clearly  established  that  all  the  symptoms  of  caisson  disease 
are  due  to  decompression,  and  not,  in  the  slightest  degree,  to  the  mechan* 
ical  effect  of  the  pressure  itself  (Paul  Bert,  Leonard  Hill  and  Macleod34). 

When  an  animal  is  under  pressure,  its  tissue  fluids  dissolve  a  large 
amount  of  gas.  They  absorb  it  in  obedience  to  the  law  of  solution  of  a 
gas  in  a  fluid,  which  states  that  the  amount  of  gas  dissolved  in  water  is 
directly  proportional  to  the  partial  pressure  of  that  gas  in  the  atmos- 
phere ;  at  two  atmospheric  pressures  twice  as  much  gas  will  pass  into 
solution  as  at  zero  pressure  (Dalton's  law).  So  long  as  the  gas  is  in 
simple  solution,  it  does  not  in  any  way  change  the  physical  condition  of 
the  blood  and  tissue  fluids.  If,  however,  the  animal  is  suddenly  decom- 
pressed (i.  e.,  the  pressure  of  air  surrounding  it  is  reduced  to  zero),  the 
dissolved  gas  will  be  so  quickly  thrown  out  of  solution  that  bubbles  of 
it  are  set  free.  These  bubbles  act  as  air  emboli,  sticking  in  the  pulmonic 
capillaries  or  blocking  up  a  terminal  artery  in  the  brain;  or  they  may  be 
large  and  tear  the  capillary  wall  and  so  lead  to  hemorrhage.  If  these 
bubbles  are  produced  in  the  posterior  spinal  roots,  intense  pain  results; 
if  in  the  anterior,  motor  paralysis.  Frothing  of  the  blood  in  the  heart  im- 
pedes the  action  of  the  organ  and  death  soon  follows. 

The  following  experiments  furnish  proof  of  this  explanation:  A  frog 
was  placed  in  a  small  steel  chamber  connected  with  a  cylinder  of  com- 
pressed air  and  provided  with  two  windows  by  which  a  strong  arc  light 
could  be  passed  through  the  chamber.  The  web  of  the  foot  was  stretched 
on  a  wire  and  fixed  so  that  the  small  blood-vessels  could  be  seen  by  apply- 
ing a  microscope  to  the  outside  of  the  window.  After  carefully  observing 
the  circulation  of  the  blood  in  the  vessels  at  atmospheric  pressure,  a  posi- 


404  THE   RESPIRATION 

tive  pressure,  amounting  in  some  experiments  to  +  50  atmospheres,  was 
introduced  but  no  effect  could  be  noted  on  the  circulating  blood.  By 
opening  a  tap  in  the  chamber,  decompression  to  zero  pressure  was  quickly- 
effected  and,  immediately,  large  bubbles  were  seen  to  develop  in  the 
blood,  blocking  the  vessels  and  producing  stasis.  The  bubbles  were  de- 
rived from  the  gas  that  had  gone  into  solution  under  pressure.  On  re- 
applying the  pressure  the  bubbles  of  gas  again  went  into  solution  and 
the  blood  circulated  normally.  When  the  pressure  was  subsequently  very 
gradually  lowered  to  zero,  the  circulation  went  on  undisturbed,  and  the 
frog  was  removed  from  the  chamber  in  normal  condition. 

The  process  involved  in  causing  caisson  disease  is  evidently  the  same  as 
that  which  can  be  observed  in  a  bottle  of  aerated  water;  if  the  cork  in 
such  a  bottle  is  drawn,  the  dissolved  gas  escapes  as  bubbles  and  effer- 
vescence results ;  if  the  bottle  is  recorked,  the  gas  reenters  solution  and 
the  fluid  becomes  quiet.  If  a  pin  hole  is  made  in  the  cork,  the  gas  will 
gradually  escape  and  no  effervescence  will  result. 

Confirmatory  results  have  been  secured  by  observations  on  mammals. 
The  arterial  blood  pressure  of  rabbits  was  not  found  to  become  altered 
by  exposure  to  compressed  air,  and  various  animals  placed  in  a  large, 
strong  steel  chamber  at  pressures  far  in  excess  of  those  to  which  man 
ever  subjects  himself  did  not  show  any  symptoms  like  those  of  caisson 
sickness,  unless  the  pressure  was  suddenly  lowered.  Many  times  also,  if 
symptoms  had  appeared  they  could  be  removed  by  again  subjecting  the 
animals  to  the  compressed  air. 

Investigations  were  also  carried  out  to  determine  exactly  how  much 
gas  the  blood  of  an  animal  subjected  to  high  pressures  contains,  and  how 
long  it  takes  to  absorb  the  maximal  amount  of  gas  and  to  release  it.  It 
was  found  that  the  gases  that  increased  in  amount  were  nitrogen  and 
oxygen,  and  that  these  become  dissolved  in  the  blood  according  to  Dal- 
ton's  law. 

The  Prevention  of  the  Symptoms 

The  most  important  practical  application  of  these  observations  con- 
cerns the  length  of  time  required  for  the  saturation  and  desaturation  to 
occur,  for  the  results  serve  as  a  basis  upon  which  the  safe  regulation  of 
work  in  compressed  air  by  man  can  be  conducted.  The  most  significant 
outcome  of  the  above  experiments  from  this  standpoint  is  that  it  takes 
considerable  time  for  the  blood  to  absorb  its  full  quota  of  gas  at  a  given 
atmospheric  pressure  and  to  liberate  it  again  when  the  animal  is  decom- 
pressed. The  cause  of  delay  is  that  the  tissue  fluids  other  than  the  blood 
take  much  longer  than  would  be  expected  to  reach  equilibrium  with  the 
partial  pressure  of  gas  in  the  blood  plasma. 


BREATHING    i\    COMPRESSED    \\i>    I  \    RAREFIED    AIR  W5 

To  understand  why  this  delay  should  occur,  let  us  Buppose  thai  the 
only  gas  concerned  is  nitrogen.  As  the  pressure  rises,  the  Mood  in  the 
capillaries  of  the  lungs  must  dissolve  nitrogen  in  proportion  to  the  pres- 
sure of  this  gas  in  the  alveoli;  the  blood  carries  the  dissolved  gas  to  the 
tissues  and  these  dissolve  it  until  the  pressure  is  again  equalized  between 
them  and  the  blood.  The  blood,  after  giving  up  its  excess  of  dissolved 
nitrogen,  returns  to  the  lungs  and  again  becomes  saturated  and  this  g 
on  until  blood  and  tissue  have  become  saturated  with  gas  at  the  external 
pressure.  The  tissues  are  two-thirds  water  and  they  contain  (in  man) 
from  15  to  20  per  cent  of  fat.  Pat,  however,  dissolves  five  times  more 
nitrogen  than  water  (Vernon)  ;  consequently,  it  takes  longer  Eor  a  given 
volume  of  tissue  than  of  blood  to  become  saturated  at  a  given  pressure. 

The  blood  in  man  constitutes  one-twentieth  of  the  body  weight;  so 
that  if  the  tissues  were  all  liquid  they  would  dissolve  20  times  as  much 
nitrogen  as  the  blood.  On  account  of  the  fat  which  they  contain,  however, 
the  tissues  take  up  more  than  this  proportion — namely,  in  an  average 
man  about  35  times  more  than  the  blood.  All  the  blood  in  the  body  takes 
about  one  minute  to  complete  a  round  of  the  circulation,  so  that  in  this 
time,  after  being  suddenly  subjected  to  an  increased  pressure — assuming 
that  the  blood  circulates  equally  throughout  the  body — the  tissues  will 
be  one-thirty-fifth  saturated;  in  the  next  minute  another  thirty-fifth  of 
thirty-four  thirty-fifths  will  be  saturated,  and  so  on.  After  five  minutes 
the  body  will  be  about  22  per  cent,  and  in  25  minutes  about  one-half, 
saturated;  but  it  will  take  about  two  hours  before  saturation  is  complete. 
These  calculations  assume  that  the  blood  is  evenly  distributed  through- 
out the  body;  but  this  is  not  the  case,  for  its  mass  movement  varies 
considerably  in  different  parts,  being  much  greater  in  the  active  muscles 
and  in  the  glands  than  in  passive  structures,  such  as  fat,  These  less  vas- 
cular parts  will  therefore  lag  behind  the  others  in  taking  up  their  full 
quota  of  gas,  and  therefore  prolong  the  time  necessary  for  complete 
saturation  of  the  body  as  a  whole. 

We  see  therefore  that,  after  some  time  in  compressed  air,  the  blood 
and  active  tissues  will  be  saturated  and  contain  volumes  of  dissolved 
gas  in  proportion  to  their  relative  bulks;  the  fat,  although  not  saturated, 
will  yet  contain  up  to  five  times  more  gas  than  an  equal  volume  of 
blood,  and  the  passive  tissues  will  be  incompletely  saturated. 

These  considerations  regarding  the  saturation  of  the  different  parts 
of  the  body  apply  also  in  its  desaturation.  Suppose,  for  example,  that 
the  external  pressure  is  suddenly  lowered:  the  blood,  on  leaving  the 
lungs,  will  contain  no  excess  of  gas;  when  it  reaches  the  tissues  it  will 
remove  gas  until  the  pressure  is  equalized,  discharge  this  into  the  alveoli 
and  return  again  for  more.     Other  things  being  equal,  it  will  take  the 


406  THE   RESPIRATION 

same  number  of  minutes  to  desaturate  that  it  took  to  saturate,  and  the. 
parts  of  the  body  that  will  lag  behind  the  others,  in  being  desaturated, 
are  those  with  a  sluggish  circulation. 

When  the  mass  movement  of  the  blood  is  increased  by  muscular  exer- 
cise, the  rate  of  saturation  and  desaturation  with  nitrogen  is  increased 
in  proportion.  During  active  work  the  increase  in  movement  of  the 
blood  may  be  four  or  five  times  over  the  normal,  so  that  the  tissues  of 
the  caisson  worker  become  much  more  quickly  desaturated  during  decom- 
pression than  the  above  figures  would  lead  one  to  expect. 

Application  of  Foregoing  Laws  in  Practice 

With  regard  to  the  application  of  these  principles  in  the  decompression 
of  caisson  workers,  it  is  impracticable  to  occupy  as  much  time  as  it  takes 
to  saturate  the  body  even  at  comparatively  low  pressures.  If  the  great 
dangers  attending  work  in  compressed  air  are  to  be  avoided,  we  must 
either  insist  on  very  gradual  decompression  or  we  must  shoAV  how  the 
dissolved  gases  may  be  got  rid  of  by  some  modification  in  the  decom- 
pression procedure.  With  this  object  in  view,  Ave  must  determine  what 
difference  of  pressure  may  be  allowed  between  the  external  air  and  the 
body  without  the  formation  of  bubbles.  Actual  experience  shows  that 
there  is  no  risk  of  bubble-formation,  however  quick  the  decompression, 
after  exposure  to  +  15  pounds  pressure  (  i.e.,  2  atmospheres  absolute). 
"Now,  the  volume  of  gas  capable  of  being  liberated  on  decompression 
to  any  given  pressure  is  the  same,  if  the  relative  diminution  of  pressure 
is  the  same"— (Haldane35).  On  reduction  from  4  to  2  atmospheres, 
the  same  volume  of  gas  will  tend  to  be  liberated  as  on  reduction  from  2 
to  1  atmospheres — that  is  to  say,  no  bubbles  will  form.  The  practical 
conclusion  is  "that  the  absolute  air  pressure  can  always  be  reduced  to 
half  the  absolute  pressure  at  which  the  tissues  are  saturated  without 
risk."  Thus,  after  saturation  at  90  pounds  absolute  pressure  (+  5  atmos- 
pheres), a  man  can  be  immediately  decompressed  to  45  pounds  (+  2 
atmospheres)  in  a  few  minutes  without  risk,  but  from  this  point  on  the 
decompression  must  be  conducted  slowly,  so  as  to  insure  that  the  nitrogen 
pressure  in  the  tissues  is  never  more  than  twice  the  air  pressure.  The 
great  advantage  of  this  method  is  that  it  makes  the  greatest  possible  use 
of  difference  of  pressure  between  tissues  and  blood  in  order  to  get  rid  of 
the  gas  that  these  contain. 

When  the  decompression  from  the  start  is  gradual,  the  desaturation 
of  the  tissues  will  progressively  lag  behind  that  of  the  blood,  and  the 
tendency  to  the  liberation  of  free  gas  will  become  greater.  In  such  a 
case  the  decompression  is  far  too  slow  at  first  and  far  too  rapid  later. 


BREATHING   IN    COMPRESSED    AND    IN*    RAREFIED    AIR  407 

Theoretically,  therefore,  the  decompression  should  be  rapid  at  first  and 
very  slow  later. 

Before  recommending  the  adoption  of  this  principle  of  stage  de- 
compression in  caisson  work,  Haldane  and  his  coworkers  made  numerous 
observations  on  the  incidence  of  decompression  symptoms  in  laboratory 
animals.  They  assert  that  the  stage  method  is  decidedly  safer  than  the 
uniform  method,  the  advantage  being  particularly  after  short  exposures. 
On  the  other  hand,  Leonard  Hill  could  make  out  no  definite  advantage 
for  the  stage  method.  The  two  methods  have  also  been  compared  in 
actual  caisson  work  at  the  Elbe  Tunnel,  where  the  pressure  was  +  2 
atmospheres.  Very  little  advantage  could  be  demonstrated  for  the 
stage  as  compared  with  the  uniform  method  at  this  comparatively  low 
pressure.  The  general  conclusion  which  we  may  draw  is  that  the  stage 
method  should  be  employed,  although  it  is  not  to  be  expected  that  it 
will  absolutely  insure  absence  of  decompression  symptoms.  Of  course 
the  great  advantage  of  the  stage  method  is  the  saving  of  time,  making 
it  possible  to  persuade  the  workmen  to  adopt  it. 

There  are  two  other  factors  that  are  to  be  considered  in  hastening  the 
desaturation  of  the  tissues;  these  are  muscular  exercise,  and  the  breath- 
ing of  an  indifferent  gas. 

It  is  clear,  from  what  has  already  been  said,  that  the  gas  dissolved  in 
the  tissues  will  become  removed  in  proportion  to  the  mass  movement 
of  the  blood,  and  it  is  probably  true  that  muscular  exercise,  performed 
in  the  decompression  chamber,  is  of  as  great  importance  in  preventing 
the  subsequent  development  of  symptoms  as  a  much  prolonged  decom- 
pression. In  a  man  at  rest,  the  circulation  through  the  central  nervous 
system  and  the  viscera  is  constantly  influenced  by  the  pumping  action 
of  the  respiratory  movements,  but  in  the  capillaries  of  the  muscles, 
joints,  fat,  etc.,  this  influence  is  not  felt  and  the  blood  flows  more  slowly. 
It  is  consequently  in  these  parts  that  bubble  formation  is  likely  to  oc- 
cur, especially  some  time  after  decompression.  The  bubbles  cause  the 
neuralgic  pains — the  -'bends"  and  --screws"  so  well  known  to  caisson 
workers.  These  could  no  doubt  be  entirely  prevented  by  muscular 
exercise  and  massage  of  the  limbs  during  decompression.  In  illustration 
of  these  facts  the  following  experiment  by  Greenwood  may  be  cited: 
During  decompression  from  +  75  pounds  pressure  in  95  minutes  "Green- 
wood flexed  and  extended  all  the  limb  joints  at  frequent  intervals,  with 
the  exception  of  the  knees.  Subsequently  pain  and  stiffness  were  ex- 
perienced in  the  knees  and  nowhere  else."  In  another  experiment  the 
knees  also  were  flexed  and  no  pain  was  felt. 

But  even  in  the  parts  with  active  circulation,  the  gas  in  the  tissues 
may  lag  considerably  behind  that  in  the  blood,  although  the  decompres- 


408  THE    RESPIRATION 

sion  has  been  properly  controlled.  This  has  been  shown  by  Leonard 
Hill  in  the  case  of  the  kidney.  The  "tissue"  gas  in  this  case  can  be 
taken  as  the  gas  dissolved  in  the  urine,  by  analyzing  which,  therefore, 
at  different  stages  of  decompression,  the  excess  of  nitrogen  over  what 
it  should  be  at  the  external  pressure,  can  be  ascertained.  On  decom- 
pression from  +  30  pounds  by  two  stages  to  zero,  a  considerable  super- 
saturation  was  found  to  exist.  The  excess  of  nitrogen  can,  however,  be 
cleared  out  of  the  kidneys  rapidly  and  completely  by  breathing  oxygen, 
which  should  therefore  be  administered  during  decompression  in  cases 
where  great  care  has  to  be  exercised  (Leonard  Hill). 

"When  symptoms  do  appear,  they  can,  in  most  cases,  be  relieved  by 
recompression,  and  all  modern  caisson  works  are  provided  with  a  special 
chamber  for  this  purpose.  "We  need  scarcely  say  anything  about  this 
treatment  here,  as  its  value  is  so  well  known.  Suffice  it  to  say  that, 
although  it  is  most  likely  to  afford  relief  when  applied  as  soon  as  pos- 
sible after  the  appearance  of  the  symptoms,  yet  it  is  often  efficacious 
when  applied  several  days  after  their  onset. 

Quite  apart  from  the  dangers  of  decompression,  it  must  of  course  be 
remembered  that  the  working  conditions  in  a  caisson  are  somewhat  dif- 
ferent from  those  at  atmospheric  pressure,  as  the  air,  owing  to  its  com- 
pression, is  warmer  and  is  loaded  to  saturation  point  with  moisture. 
This  hot,  wet  air  interferes  with  the  heat-regulating  mechanism  of  the 
body,  making  hard  muscular  work  very  uncomfortable  because  of  the 
tendency  of  the  body  temperature  to  rise.  The  reaction  of  the  body 
against  this  tendency  to  hyperthermia  consists  in  dilatation  of  the  su- 
perficial capillaries  and  increased  heart  action. 

"When  such  working  conditions  are  repeated  day  by  day,  the  appetite 
is  likely  to  fail,  partly  because  of  the  tendency  of  the  body  to  suppress 
the  activity  of  the  metabolic  processes,  so  as  to  keep  down  heat  produc- 
tion, and  partly,  no  doubt,  because  the  digestive  processes  are  working 
below  par  on  account  of  there  being  less  blood  circulating  through  the 
visceral  blood  vessels,  it  having  been  sent  to  the  surface  of  the  body  to 
be  cooled  off.  The  worker  therefore  tends  to  take  less  food,  his  metabo- 
lism becomes  depressed,  and  his  factors  of  safety  against  bacterial 
infections  become  lessened. 

The  risk  of  the  appearance  of  symptoms  on  decompression  is  also 
greater  when  the  air  in  the  caisson  has  been  moist  and  hot,  for  the  heart 
has  been  overworking  to  maintain  the  bloodflow  in  the  dilated  vessels; 
it  gets  fatigued  and  is  consequently  unable  to  maintain,  during  decom- 
pression, a  rate  of  bloodflow  that  is  adequate  for  carrying  the  gas- 
saturated  blood  to  the  lungs,  where  the  excess  of  gas  becomes  dissi- 
pated. 


BREATHING    IN    COMPRESSED    AND    IN    RAREFIED    AIR  409 

The  criterion  of  proper  working  conditions  in  the  caisson  is  there- 
fore the  wet-bulb  temperature.  This  should  stand  below  75°  p.  To 
maintain  this  condition  it  is  necessary  to  ventilate  the  caisson,  pref- 
erably with  air  that  has  been  cooled  by  cold-water  radiators:  in  any 
case,  the  ventilation  should  be  adequate  to  keep  down  the  wet -bulb 
temperature.  The  increased  expense  of  ventilation  with  cooled  air 
would  soon  be  balanced  by  the  greater  working  efficiency  of  the  men. 
Constant  circulation  of  the  air  in  the  caissons  by  means  of  fans  assists 
also  in  improving  the  conditions,  for  it  helps  to  increase  dissipation  of 
heat  from  the  body. 


CHAPTER  XLVII 

THE  CIRCULATORY  AND  RESPIRATORY  CHANGES  ACCOM- 
PANYING MUSCULAR  EXERCISE* 

During  activity  the  muscles  require  many  times  more  blood  than  dur- 
ing rest.  When  the  activity  is  widespread  the  greater  blood  supply  is 
provided  by  increased  heart  action  accompanied  by  dilatation  of  the 
muscular  arterioles  and  constriction  of  those  of  the  splanchnic  area,  so 
that  the  entire  available  blood  supply  of  the  body  is  made  to  circulate 
more  rapidly.  When,  on  the  other  hand,  the  activity  is  confined  to  a 
limited  group  of  muscles,  the  increased  blood  supply  is  mainly  provided 
by  a  local  dilatation  of  the  blood  vessels  of  the  active  muscles  accom- 
panied by  a  reciprocal  constriction  of  those  of  inactive  parts.  Under 
these  conditions  there  may  therefore  be  no  quickening  of  the  bloodflow 
as  a  whole.  In  order  that  this  accurate  adjustment  of  blood  supply  to 
tissue  demands  may  be  promptly  and  adequately  brought  about,  all 
available  types  of  coordinating  mechanism  are  called  into  play ;  that  is 
to  say,  mechanical,  nervous  and  hormone  factors  cooperate  to  an  extent 
which  is  dependent  upon  the  type  of  work  being  performed. 

Besides  the  changes  in  pulse  rate  and  blood  pressure  which  are  evi- 
dently designed  to  supply  more  blood  to  the  acting  muscles,  changes 
dependent  upon  a  secondary  effect  of  the  muscular  movements  have  also 
to  be  considered.  Although  the  various  factors  work  together  and  are 
more  or  less  interdependent,  the  final  effect  can  be  understood  only  after 
we  have  studied  the  relative  influence  of  each  separately. 

The  Mechanical  Factor. — It  is  particularly  with  regard  to  this  factor 
that  the  circulatory  changes  may  be  an  unavoidable  consequence  of, 
rather  than  a  useful  adjustment  to,  the  muscular  effort.  The  effects  vary 
with  the  type  of  exercise  performed.  In  repeatedly  lifting  and  lowering 
dumbbells  from  the  floor  to  above  the  head,  the  contracting  muscles  of 
the  back  and  extremities  and  of  the  abdomen  compress  the  veins  and 
cause  the  blood  to  flow  more  rapidly  into  the  heart,  so  that  the  arterial 
pressure  suddenly  rises.  So  long  as  this  compression  exists,  the  veins 
remain  relatively  empty  and  the  arteries  overfilled,  but  whenever  it 
ceases  and  the  muscles  relax,  the  veins  fill  up  again  and  the  arterial  pres- 


*This   chapter   is  placed   here   rather   than    following  circulation   because  of  the  interdependence  of 
the    circulatory    and    respiratory    adjustments. 

410 


CHANGKS   ACCOMPANYING    MUSCULAR    EXERCISE  411 

sure  markedly  falls,  until  the  extra  space  in  the  veins  has  been  occupied 
by  blood.  It  is  for  this  reason  that  the  arterial  blood  pressure  is  always 
found  to  be  little,  if  any.  above  normal  when  taken  within  a  few  seconds 
after  such  exercise.  It  subsequently  rises  because  the  other  factors 
responsible  for  the  increased  pressure  (quick  heart  and  arteriole  constric- 
tion) are  still  in  operation  at  the  time  the  veins  again  become  filled  with 
blood.  The  purely  mechanical  influence  outlasts  the  exercise  for  a  com- 
paratively short  time,  whereas  the  nervous  and  hormone  influences  con- 
tinue acting.  This  interpretation  is  supported  by  the  observation  fohat 
the  fall  of  blood  pressure  is  greater  when  the  subject  is  left  standing 
after  a  given  amount  of  dumbbell  exercise  than  when  he  is  allowed  to  sit 
with  his  elbows  resting  on  his  knees.  In  the  standing  position  the  pres- 
sure on  the  abdominal  veins  is  less  and  the  hydrostatic  effect  of  gravity 
causes  more  blood  to  collect  in  the  large  veins  (Cotton,  Rapport  and 
Lewis3").  Being  purely  mechanical  in  its  causation,  the  preliminary  fall 
following  dumbbell  exercise  can  always  be  demonstrated  if  the  observa- 
tions are  made  at  close  enough  intervals  of  time. 

The  mechanical  response  of  the  circulation  to  exercise  acts  therefore 
through  the  rate  of  filling  of  the  right  heart  with  blood,  and  if  this  organ  is 
in  a  healthy  condition,  it  will  respond  to  the  greater  inflow  by  correspond- 
ingly increased  discharge.  Like  every  other  physiologic  mechanism,  the 
heart  works  with  a  large  factor  of  safety — a  reserve  power — and  it  is 
the  rate  of  venous  filling  that  determines  how  much  of  this  reserve  must 
be  called  upon  to  maintain  the  circulation.  In  isolated  heart-lung  prep- 
arations Starling  and  his  coworkers  have  very  clearly  demonstrated  the 
close  dependence  of  cardiac  output  upon  rate  of  venous  filling  and  the 
enormous  range  through  which  the  systolic  discharge  can  be  made  to 
vary  by  altering  this  factor.  As  explained  elsewhere,  when  the  reserve 
power  of  the  heart  is  lessened,  the  rise  in  blood  pressure  following  exer- 
cise is  longer  in  attaining  its  maximum,  which  is  set  at  a  higher  level  and 
persists  for  a  longer  time.  Observation  of  the  extent  of  these  changes 
furnishes  a  most  useful  functional  test  of  cardiac  efficiency. 

Other  mechanical  factors  that  augment  the  cardiac  output  depend  on 
the  increased  respiratory  movements.  During  each  respiration  the  in- 
crease in  capacity  in  the  thorax  causes  both  an  opening  up  of  the  thin- 
walled  veins,  so  that  blood  is  aspirated  towards  them  from  the  extra- 
thoracic  venous  system,  and  a  dilatation  of  the  blood  vessels  of  the  lungs, 
so  that  the  blood  finds  its  way  from  right  to  left  heart  more  readily. 
Although  this  dilatation  will  at  first  tend  to  cause  more  blood  to  collect 
in  the  intrathoracic  vessels  and  less  to  be  pumped  out  of  them,  the  expira- 
tory act  when  it  supervenes  will,  by  compressing  the  veins,  cause  the 
extra  blood  to  be  expelled  into  the  left  ventricle  and  thence  into  the 


412  THE   KESPIRATION 

arteries.  It  is  obvious  that  increased  depth  and  frequency  of  the  respira- 
tory movements  will  accelerate  the  blpodflow  and  tend  to  raise  the  arte- 
rial blood  pressure. 

The  above  factors  will  come  into  play  during  most  kinds  of  muscular 
exercise  such  as  walking,  running,  or  swinging  dumbbells,  etc.  There 
are  certain  types  of  muscular  effort,  however,  in  which  the  mechanical 
factors  produce  decidedly  disturbing  effects  on  the  circulation.  During 
a  sustained  effort  as,  for  example,  in  pulling  against  a  resistance  or  in 
attempting  to  lift  a  heavy  load,  the  respirations  are  suspended,  often  after 
a  deep  inspiration,  and  the  contracted  abdominal  muscles  press  the  dia- 
phragm up  into  the  thoracic  cavity.  After  a  preliminary  squeezing  out 
of  blood  first  of  all  from  the  veins  of  the  abdomen  into  the  thorax  and 
then  from  those  of  the  latter  into  the  systemic  arteries,  with  a  consequent 
rise  in  arterial  pressure,  there  comes  to  be  a  damming  back  of  blood  into 
the  peripheral  veins,  causing  them  to  swell  and,  if  continued,  marked 
cyanosis  may  develop.  "When  such  efforts  are  maintained  for  long,  the 
arterial  pressure  begins  to  fall,  and  this  fall  is  very  pronounced  indeed 
at  the  end  of  the  effort,  because,  the  compression  being  removed  from  the 
abdominal  and  thoracic  veins,  these  open  up  and  form  a  large  unfilled 
blood  reservoir. 

A  similar  mechanism  comes  into  play  during  expulsive  acts  such  as 
defecation,  parturition,  etc.  In  these  the  glottis  is  closed,  usually  after 
a  preliminary  inspiration,  and  a  powerful  expiratory  movement  is  per- 
formed, with  the  consequence  that  the  intrathoracic  and  intraabdominal 
pressures  rise  considerably,  greatly  augmenting  the  systolic  discharge 
and  causing  the  blood  pressure  to  rise.  Because  of  the  obstruction  to 
the  bloodfloAv  in  the  large  veins  of  the  abdomen  and  thorax,  however, 
the  later  effect  of  the  effort  is  to  diminish  the  systolic  discharge,  but  the 
fall  in  blood  pressure  which  this  would  be  expected  to  occasion  is  masked. 
The  pressure  remains  high  because  other  factors  increasing  the  peripheral 
resistance  come  into  play.  The  fall  in  blood  pressure  following  these  acts 
may  be  very  marked  indeed.  Similar  mechanical  effects  are  produced 
in  the  acts  of  coughing,  sneezing,  etc. 

The  capacity  of  the  veins  varies  considerably  with  the  position  of  the 
body,  and  it  is  in  order  that  we  may  cause  alterations  in  this  capacity 
and  therefore  encourage  a  more  rapid  bloodflow  that  we  stretch  the  body 
after  sitting  for  some  time  in  a  cramped  position. 

The  Nervous  Factor. — The  vagus,  vasoconstrictor  and  respiratory  cen- 
ters are  all  excited  during  muscular  effort.  In  the  earlier  stages  the 
excitation  depends  entirely  on  nervous  impulses  transmitted  to  the  cen- 
ters, but  later  it  depends  on  changes  in  the  composition  and  temperature 
of  the  blood  flowing  through  them — the  hormone  factor.     The  initial 


CHANGES   ACCOMPANYING    MUSCULAR    EXERCISE  413 

stimulation  of  the  centers  must  be  due  to  cerebral  impulses  independ- 
ently transmitted  to  the  above  centers,  since  the  quickening  of  the  pulse 
and  respirations  may  be  observed  to  begin  before  the  actual  muscular 

contractions. 

The  Hormone  Factor.— "We  have  to  consider  first  the  nature  of  the 
hormone,  and  secondly  the  mode  of  its  action. 

The  Nature  of  the  Hormones. — The  most 'important  hormone  is  car- 
bonic acid,  but  when  the  exercise  is  strenuous  and  continued,  or  from 
the  very  start  is  of  such  a  nature  that  it  uses  up  oxygen  more  quickly 
than  the  blood  can  supply  it  to  the  muscles,  lactic  acid  also  appears. 
Evidence  for  these  statements  can  readily  be  supplied  in  man  by  analy- 
sis of  the  expired  air  (for  carbon  dioxide)  and  of  the  urine  (for  lactic 
acid)  before  and  during  muscular  work.  The  real  hormone  in  both  cases 
is  believed  to  be  an  increase  in  the  H-ion  concentration  of  the  blood. 
There  is,  however,  no  direct  proof  of  this  assertion — that  is  to  say,  no 
one  has  actually  shown  that  a  measurable  change  in  the  H-ion  concentra- 
tion of  the  arterial  blood  (for  of  course  a  change  in  the  venous  blood 
would  be  of  no  significance)  does  occur  before  the  changes  believed  to 
be  dependent  upon  acid  production  make  their  appearance.  The  well- 
known  buffer  action  of  the  blood  (that  is,  its  ability  to  take  up  con- 
siderable quantities  of  acid  or  of  alkali  before  any  perceptible  change 
occurs  in  H-ion  concentration)  furnishes  another  reason  why  doubt 
must  be  cast  upon  the  H-ion  hypothesis.  The  most  delicate  means  for 
demonstrating  a  change  in  H-ion  concentration  of  the  blood  consists  in 
finding  the  dissociation  constant  for  hemoglobin  and  the  results  have 
shown  that  acidosis  develops  during  exercise  at  least  at  high  altitudes 
(Barcroft1).  So  far  as  we  are  aware,  however,  it  has  not  been  possible  by 
direct  measurement  (page  29)  to  detect  a  rise  in  H-ion  concentration. 
Of  course  it  may  well  be  that  the  sensitiveness  of  the  various  nerve 
centers  and  other  structures  towards  the  H-ion  concentration  is  very 
much  greater  than  our  most  refined  and  sensitive  laboratory  methods 
can  reveal.  Such  is  at  least  commonly  believed  to  be  the  case  for  the 
respiratory  center  (see  page  351),  and  it  may  also  be  so  for  those  of 
vascular  tone  and  cardiac  action.  It  is  nevertheless  possible  that  an 
increase  in  the  free  carbonic  acid  itself — the  carbonate  anion  (-HC03), 
in  other  words — is  the  effective  hormone.  In  the  first  stages  of  muscular 
work,  this  increase  would  be  due  to  greater  production  of  C02,  whereas 
later,  especially  when  the  work  is  strenuous,  lactic  acid  would  decom- 
pose the  NaHC03  of  the  blood,  liberating  -HC03,  which  would  become 
added  to  that  still  being  produced  by  the  active  muscles,  and  as  the 
NaHC03  (buffer  substance)  became  gradually  used  up,  would  cause  a 
relatively  greater  and  greater  proportion  of  -HC03  to  exist  in  a  free 


414  THE   RESPIRATION 

state.  That  the  C02  tension  of  the  alveolar  air  should  be  found  to  be 
lowered  by  prolonged  muscular  exercise  in  no  way  detracts  from  this 
explanation,  for  it  is  dependent  upon  the  greatly  increased  rate  of 
movement  of  air  into  and  out  of  the  alveoli    (pee  also  page  366). 

One  serious  difficulty  in  accepting  the  HC03  ion  as  the  exciting  hor- 
mone of  the  nerve  centers  during  muscular  exercise  depends  on  the  ob- 
servation that  the  alveolar  .C02  after  some  time  is  lower  than  normal. 
If  we  accept  Haldane's  teaching  that  there  is  accurate  correspondence 
between  the  tensions  of  C02  in  arterial  blood  and  alveolar  air  not  only 
during  rest  but  also  during  muscular  activity,  then  obviously  we  must 
discard  the  HCOs  hypothesis.  Leonard  Hill  and  Flack,37  however,  have 
shown  quite  clearly  both  in  experimental  animals  and  in  man  that  equi- 
librium between  the  blood  and  alveolar  tensions  of  C02  may  fail  to 
occur.  "When  blood  with  excess  of  C02  is  injected  into  the  jugular  vein 
of  dogs,  the  respiratory  center  is  stimulated,  as  shown  by  the  increased 
breathing,  which  indicates  that  the  CO;-rich  blood  must  have  passed 
through  the  lungs  without  the  excess  of  C02  being  removed  from  it. 
Hill  believes  that  the  diffusion  of  CO,  out  of  the  blood  into  the  alveolar 
air  may  be  depressed  in  muscular  exercise,  and  that  this  rather  than  the 
appearance  of  lactic  acid  in  the  blood  is  responsible  for  the  low  C02  ten- 
sions usually  found  present  (see  page  369).  He  points  out  in  support 
of  this  view  that  a  person  after  exercise  can  hold  his  breath  for  a  much 
shorter  time  than  is  usual,  and  the  C02  meanwhile  mounts  in  the  alveolar 
air  very  rapidly. 

The  only  way  by  which  progress  may  be  made  in  a  problem  like  that 
under  discussion  is,  however,  to  adopt  some  hypothesis  and  then  to 
gather  evidence  for  or  against  it.  At  the  present  stage  of  our  knowl- 
edge, the  hypothesis  usually  adopted  is  that  a  slight  change  in  H-ion 
concentration  of  the  blood  is  the  effectual  hormone.  It  is  an  hypothe- 
sis which  is  supported  by  the  parallelism  between  the  effects  observed 
during  muscular  exercise  and  those  produced  by  experimental  increase 
in  H-ion  concentration. 

The  Effects  of  the  Hormone. — These  may  be  classified  as  follows:  (1) 
strictly  local  effects  on  the  muscles  themselves;  (2)  effects  on  the  heart; 
and  (3)  effects  on  the  nerve  centers.  The  local  production  of  acids  in 
the  muscles  will  cause  dilatation  of  the  arterioles,  for  it  has  been  shown 
by  various  observers  that  acids  cause  relaxation  of  vascular  muscle. 
Even  the.  capillaries  themselves  are  said  to  be  dilated  by  carbonic  acid 
(Severini).  The  effects  produced  on  the  heart  by  changes  in  H-ion  con- 
centration of  the  blood  have  been  particularly  studied  by  Starling  and 
Patterson,38  who,  working  on  isolated  heart-lung  preparations,  have 
shown  that  the  heart  relaxes  more  and  more  and  discharges  less  blood 


CHANGES   ACCOMPANYING    MUSCULAR    EXERCISE  415 

as  the  1  lion  concentration  of  the  perfusion  fluid  is  increased  by  adding 
COs  to  the  air.  ventilating  the  lungs. 

The  influence  of  changes  in  II-ion  concentration  of  the  blood  on  the 
vagus  and  vasomotor  centers  is  usually  believed  to  be  stimulatory. 
There  is  no  doubt  that  an  increase  in  Ch  stimulates  the  vasoconstrictor 
centers,  not  only  of  the  medulla,  but  also,  although  much  more  feebly, 
of  the  spinal  cord.  But  it  is  a  question  whether  any  part  of  the  rise  in 
systolic  pressure  during  muscular  exercise  can  be  attributed  to  this 
cause,  for  the  enormously  increased  bloodflow  which  is  known  to  occur 
makes  it  problematical  whether  any  vasoconstriction  really  occurs.  If 
it  does  so,  it  must  be  confined  to  the  splanchnic  area,  where  it  would 
have  the  effect  of  bringing  about  a  redistribution  of  the  total  available 
blood  by  expressing  it  from  the  viscera  and  sending  it  to  the  active 
muscles. 

The  effect  of  increased  H-ion  concentration  on  the  vagus  center  must 
be  insignificant.  It  is  commonly  believed  that  it  would  cause  not  wrhat 
is  actually  observed,  a  quickening,  but  rather  a  slowing  of  the  heart  rate. 
But  even  this  is  doubtful.  The  slowing  of  the  heart  that  is  observed  in 
asphyxia,  for  example,  is  in  part  at  least  due  to  the  increased  intra- 
cranial pressure,  for  when  the  carotid  artery  is  connected  with  a  mer- 
cury valve  so  that  the  blood  escapes  as  the  pressure  rises  above  the 
normal  level,  no  slowing  of  the  heart  is  said  to  occur  in  asphyxia.  As 
Leonard  Hill  and  Flack37  have  shown,  howTever,  a  part  of  the  slowing  is 
due  to  the  direct  effect  of  C02.  If  increase  in  the  H-ion  concentration 
does  affect  the  heart  during  muscular  exercise,  it  must  act  by  inhibiting 
the  vagus  tone,  Avhich  is  opposite  to  the  action  which  it  is  usually  be- 
lieved to  have.  The  activity  of  the  respiratory  center  is  of  course  ex- 
cited by  increase  in  H-ion  concentration,  and  this,  as  we  have  seen,  will 
cause  important  changes  in  the  circulation  because  of  the  mechanical 
effects  which  follow. 

Along  with  hormones  Ave  must  consider  the  effect  of  change  in  the 
temperature  of  the  hlood.  That  this  rises  during  muscular  exercise  is 
well  known,  but  that  it  should  be  responsible  for  many  of  the  cardio- 
vascular adjustments  that  occur  is  quite  commonly  overlooked.  It  is, 
for  example,  very  likely  that  rise  in  blood  temperature  is  responsible 
for  the  acceleration  of  the  heart  that  occurs  during  exercise  when  both 
vagi  have  been  severed,  and  it  no  doubt  is  responsible  for  a  part  at 
least  of  the  vasodilatation  and  respiratory  acceleration. 

Finally,  it  is  interesting  to  speculate  as  to  the  nature  of  the  changes 
that  occur  when  the  "second  wind"  is  acquired  during  strenuous  mus- 
cular exercise.  In  running,  for  example,  considerably  more  distress  is 
experienced  a  short  time  after  the  start  than  some  time  later.     Three 


416  THE   RESPIRATION 

very  definite  changes  occur  at  the  time  the  relief  is  experienced — namely, 
a  slowing  and  steadying  of  the  previously  much  quickened  and  irregu- 
lar pulse,  sweating,  and  a  marked  fall  in  the  respiratory  quotient.  The 
last  mentioned  change  possibly  gives  a  clue  to  the  cause  of  the  others. 
In  the  early  stages  B.  Q.  is  raised,  which  indicates  that  relatively  more 
C02  is  being  expelled  from  the  blood  into  the  alveolar  air  than  oxygen 
is  being  absorbed,  perhaps  because  of  inadequate  movement  of  blood 
through  the  lungs.  At  the  time  of  the  adjustment  it  is  possible  that  a 
pronounced  vasodilatation  occurs  in  the  muscles  and  coronary  arteries. 
The  former  change  by  lowering  the  arterial  blood  pressure  will  relieve 
the  pumping  action  of  the  heart,  and  the  latter  will  improve  its  power  of 
contraction  by  supplying  it  with  more  oxygen. 

RESPIRATION  REFERENCES 

(Monographs) 

Barcroft,  J.:  The  Respiratory  Function  of  the  Blood,  University  Press,  Cambridge, 
1914. 

Borrutau,  H.:  Nagel's  Handbuch  der  Physiologie,  1905,  i,  29. 

Douglas,  C.  G-. :  Die  Regulation  der  Atmung  beim  Menschen,  Ergebnisse  der  Physiol- 
ogie, 1914,  p.  338. 

Hill,  Leonard:  Caisson  Sickness,  International  Medical  Monographs,  E.  Arnold, 
London,  1912. 

Keith,  Arthur:  The  Mechanism  of  Respiration  in  Man,  Further  Advances  in  Physi- 
ology, E.  Arnold,  London,  1909. 

Schenck,  F. :     Innervation  der  Atmung,  Ergebnisse  der  Physiologie,  1908,  p.  65. 

(Original  Articles) 

!Keith,  Arthur:     Cf.  Further  Advances. 

2Hoover,  C.  F.:     Arch.  Int.  Med.,  1913,  xii,  214;  ibid.,  1917,  xx,  701. 
3Lee.  F.  S.,  Guenther,  A.  E.,  and  Meleney,  H.  F.:  Am.  Jour.  Physiol.,  1916,  xl,  446. 
4Meltzer,  S.  J.:     Jour.  Physiol.,  1892,  xiii,  218. 

5Haldane,  J.  S.,  and  Priestley,  J.  G.:     Jour.  Physiol.,  1905,  xxxii,  225. 
Haldane  and  Douglas:     Ibid.,  1913,  xlv,  235. 
6Henderson,  Y.,   Chillingworth  and  Whitney:  Am.   Jour.  Physiol.,   1915,  xxxviii,   1. 

Henderson  and  Morriss:     Jour.  Biol.  Chem.,  1917,. xxx,  217. 
?Krogh,  A.,  and  Lindhard:     Jour.  Physiol.,  1913,  xlvii,  30;  ibid.,  1917,  li,  59. 
sPearce,  R.  G.:     Am.  Jour.  Physiol.,  1917,  xliii,  73;  ibid.,  1917,  xliv,  369. 
sSiebeck,  R.:     Skand.  Arch.  f.  Physiol.,  1911,  xxv,  87;  Carter,  E.  P.:     Jour.  Exper. 
Med.,  1914,  xx,  21. 
loPeabody,  F.  W.,  and  Wentworth,  J.  A.:     Arch.  Int.  Med.,  1917,  xx,  443. 
uLewis,  T.:     Jour.  Physiol.,  1908,  xxxiv,  213,  233. 
isPorter,  W.  T.:     Jour.  Physiol.,  1895,  xvii,  455. 
^Christiansen  and  Haldane,  J.:     Jour.  Physiol.,  1914,  xlviii,  272. 
"Boothby,  W.  M.,  and  Berry,  F.   B.:      Am.   Jour.   Physiol.,   1915,   xxxvii,  433;   also 

Boothby,  W.  M.,  and  Shamoff,  V.  N".:     Ibid.,  p.  418. 
isAlcock,  N.  H.,  and  Seemann,  J.:     Jour.  Physiol.,  1905,  xxxii,  30. 
iGScott,  F.  H.:     Jour.  Physiol.,  1908,  xxxvii,  301. 
i^Stewart,  G.  N.,  and  Pike,  F.  H.:     Jour.  Physiol.,  1907,  xx,  61. 
iraCoombs,  H.  C,  and  Pike,  F.  H.:     Proc.  Soc.  Exper.  Biol.  Med.,  1918,  xv,  55. 
isKrogh,  A.:     Skand.  Arch.   f.   Physiol.,   1910,  xxiii,   248;   and   A.   Krogh  with   Marie 
Krogh,  ibid.,  179. 


CHANGES    ACCOMPANYING    MUSCULAR   EXERCISE 


417 


"Haldane,  J.  8.,  and  Priestley,  J.  G.:     Jour.  Physiol.,  1905,  xxxii,  225. 

soScott,  R.  W.:     Am.  Jour.  Physiol.,  1917,  xliv,  196. 

-"Newbury,  Means,  and  Porter,  W.  T.  :  Jour.  Exper.  Med.,  1910,  xxiv,  583. 

--•llasselbalcli,  K.  A.,  and  Lundsgaard,  Chr. :     Biochcm.  Ztschr.,    L912,  xxxviii,   77,  and 

Skand.  Arch.  f.  Physiol.,  1912,  xxvii,  13. 
23Hooker,  D.  R.,  Wilson,  D.  W.,  and  Connett,  H.:     Am.  Jour.  Physiol.,  1917,  xliii,  357. 
2*0ampbcll,  J.  M.  H.,  Douglas,  C.  G.,  and  Hobson,  F.  G.:     Jour.  Physiol.,  1914,  xlviii, 

303. 
ssLindhard,  J.:     Jour.  Physiol.,  1911,  xxxviii,  337;  Haldane,  J.  S.,  and  Douglas,  C.  G.: 

Ibid.,  1913,  xlvi. 
26Douglas,   C.   G. :     Art,    Ergebnisse   der  Physiologie,  see   Monographs. 
27Barcrof  t,  J. :     see  Respiratory  Function  of  Blood. 
28Milroy,  T.  H.:     Quart,  Jour.  Physiol.,  1913,  vi,  373. 
29Fletcher,  W.  M.,  and  Hopkins,  F.  G.:     Jour.  Physiol.,  1907,  xxxv,  247;  also  Fletcher, 

W.  M.:     Jour.  Physiol.,  1913,  xlvii,  361. 
soRyffel,  J.  H.:     Proc.  Physiol.  Soc.  in  Jour.  Physiol.,  1909,  xxxix,  29. 
siPembrey,  M.  S.,  and  Allen,  R.  W.:     Jour.  Physiol.,  1909,  xxxii,  18. 
32Buckmaster,  G.  A.:     Jour.  Physiol.,  1917,  li,  105. 
33Douglas,  C.  G.,  Haldane,  J.  S.,  Henderson,   Y.,  and  Schneider,  E.   O.i     Phil.   Trans. 

Roy.  Soc,  1913,  203,  B,  185. 
3*Hill,   Leonard,   Macleod,   J.   J.   R.:     Jour.   Physiol.,   1903,  xxix,  .507;    Hill,   Leonard, 

Greenwood,  M.,  Flack,  M.,  etc.:     see  Hill's  Caisson  Sickness. 
sr-Haldane,   J.   S. :      Deep   Water   Diving,   Committee   of   the  Admiralty    (British),   see 

Hill 's  Caisson  Sickness. 
36Cotton,  T.  F.,  Rapport,  and  Lewis,  T.:     Heart,  1918. 
3'Hill,  Leonard,  and  Macleod,  J.  J.  R. :     Jour.  Physiol.,  1908,  xxxvii,  77. 
33Patterson,  S.  W.,  Piper,  H.,  and  Starling,  E.  H.:     Jour.  Physiol.,  1914,  xlviii,  465. 


PART  V 

DIGESTION 


CHAPTER  XLVIII 
GENERAL  PHYSIOLOGY  OF  THE  DIGESTIVE  GLANDS 

The  function  of  digestion  is  to  bring  the  food  into  such  a  condition 
that  it  can  be  absorbed  through  the  intestinal  epithelium  into  the  blood 
and  lymph.  Carbohydrates  are  broken  down  as  far  as  monosaccharides; 
neutral  fats  are  split  into  fatty  acids  and  glycerine;  and  proteins  are 
broken  down  into  the  amino  acids.  The  agencies  which  effect  these 
decompositions  are  the  digestive  enzymes,  or  ferments,  contained  in  the 
various  digestive  fluids  or  juices.  The  digestive  juices  are  produced  by 
glands,  which  are  most  numerous  in  the  upper  levels  of  the  gastro- 
intestinal tract,  the  lower  levels  having  as  their  main  function  that  of 
absorption  of  the  digested  products.  In  order  that  the  masses  of  food 
may  be  kept  in  a  state  of  proper  consistency,  and  that  they  may  move 
readily  along  the  digestive  canal,  numerous  mucous  glands  are  also 
scattered  along  the  whole  extent  of  the  canal.  Some  of  the  digestive 
glands,  such  as  the  main  salivary  glands,  the  pancreas,  and  the  liver, 
discharge  their  secretions  into  the  digestive  canal  by  special  ducts, 
whereas  others,  such  as  the  isolated  salivary  gland  follicles  in  the  mouth, 
the  gastric  glands  and  the  crypts  of  Lieberkuhn  in  the  intestine,  do  not 
have  an  anatomically  distinct  duct,  but  discharge  their  secretions  directly 
into  the  digestive  tube. 

It  will  be  convenient  to  consider,  first  of  all,  certain  properties  that  are 
common  to  the  digestive  glands,  and  then,  the  conditions  under  which 
each  gland  functionates  during  digestion. 

MICROSCOPIC  CHANGES  DURING  ACTIVITY 

Structurally  the  active  part  of  the  glands,  represented  by  the  acinus 
or  tubule,  is  composed  of  a  basement  membrane  lined  internally  with  the 
secreting  epithelium.  Outside  the  basal  membrane  are  the  lymph  spaces 
and  blood  capillaries.    After  the  gland  has  been  at  rest,  the  cells  become 

418 


PHYSIOLOGY    OK    T11K    DIGESTIVE   GLANDS 


41!) 


filled  with  granules  or  small  globules,  which  arc  often  so  numerous  ;is 

almost  entirely  to  obliterate  the  nucleus.  When  the  gland  becomes  active, 
on  the  other  hand,  the  granules  or  globules  leave  the  cells,  excepl  Epr  ;i 
lew   which    remain   toward   the   lumen    border.     (Figs.    14:5   and    144.) 


A.  B. 

Fig.    143. — Cells   of   parotid    gland    showing  zymogen   granules:     A,   after   prolonged    rest;    D,   after   a 
moderate    secretion;    C,    after   prolonged    secretion.      (From    I.angley.) 

These  observations  indicate  that  the  granular  or  globular  material  must 
represent  part  at  least  of  the  secretion  of  the  glands.  Sometimes,  even 
before  they  are  extruded,  the  granules  become  changed  into  some  differ- 
ent material,  as  is  indicated  by  the  fact  that  they  stain  differently  from 


Fig.  144. — Parotid  gland  of  rabbit  in  varying  states  of  activity  examined  in  fresh  state.  The 
upper  left-hand  acini  are  resting.  The  upper  right-hand  acini  are  from  a  gland  stimulated  to 
activity  by  injecting  pilocarpine,  and  the  two  lower  acini  from  one  after  stimulation  of  its  sym- 
pathetic  nerve.      (After   Langley.) 

those  of  the  resting  gland.  It  must  not  be  thought,  however,  that  an 
extrusion  of  granules  necessarily  accompanies  secretory  activity,  for 
under  certain  conditions  a  copious  secretion  of  water  and  inorganic  salts, 
as  well  as  a  certain  amount  of  organic  material,  may  be  produced  with- 


420  DIGESTION 

out  any  change  in  the  arrangement  of  the  granules.  In  such  cases  it  has 
been  observed,  as  in  the  pancreas,  that  fine  channels  develop  in  the 
protoplasm  of  the  cell  (see  page  429). 

From  this  histologic  evidence  it  would  appear  that  the  gland  cell 
during  rest  is  endowed  with  the  property  of  building  up  out  of  the  pro- 
toplasm, as  granules  or  globules,  the  material  which  is  to  serve  as  one  of 
the  main  organic  constituents  of  the  secretion.  It  is  commonly  believed 
that  this  is  the  precursor  of  the  active  ferment  of  the  secretion;  hence  its 
name,  zymogen.  It  has  been  shown  that  the  process  of  separation  of  the 
zymogen  granules  starts  around  the  nucleus  with  the  production  of  a 
basophile  substance,  which  in  hardened  specimens  sometimes  takes  the 
form  of  filaments.  From  this  basophilic  ergastoplasm,  as  it  is  called,  the 
granules  are  gradually  formed,  and  then  for  some  time  continue  to 
undergo  slight  further  changes,  as  is  evidenced  by  the  fact  that  the 
staining  reaction  of  those  near  the  base  of  the  cells  differs  from  that  of 
those  at  the  free  margin.  "When  the  gland  cell  is  excited  to  secrete, 
the  granules  before  being  extruded,  as  noted  above,  often  undergo  a 
definite  change,  becoming  swollen  and  more  globular  in  shape. 

MECHANISM  OF  SECRETION 

These  histologic  studies  merely  tell  us  that  active  changes,  associated 
with  the  production  and  liberation  of  certain  of  the  constituents  of  its 
secretion,  are  occurring  in  the  gland  cell,  but  they  throw  no  light  on  the 
mechanism  whereby  the  gland  cells  secrete  water  and  inorganic  salts. 
This  may  be  dependent,  to  a  certain  extent  at  least,  on  differences  in 
osmotic  pressure  (see  page  11).  A  possible  explanation  of  the  flow  of 
water  is  as  follows:  If  a  watery  solution  of  some  osmotically  active  sub- 
stance is  put  in  a  tube,  which  is  closed  at  one  end  by  a  membrane 
impermeable  to  this  substance  and  at  the  other  by  one  permeable  to  it, 
and  the  tube  immersed  in  water,  a  continuous  current  will  be 
found  to  issue  from  the  permeable  end  so  long  as  there  remains  any 
osmotically  active  substance  in  the  tube.  If  we  assume,  then,  that  the 
membranes  at  the  two  ends  of  the  secreting  cell  are  of  such  a  nature  that 
the  one  next  the  basement  membrane  is  impermeable  to  some  osmotically 
active  substance  manufactured  by  the  cell,  and  the  other  toward  the 
lumen  is  permeable,  it  will  be  clear  that,  so  long  as  this  substance 
exists  in  the  cell,  it  will  attract  water  from  the  blood,  and  the  water 
together  with  the  osmotically  active  substance  will  be  discharged  into 
the  lumen. 

It  is  possible  that  when  anything  excites  the  cell  to  secretory  activity, 
such  as  a  nerve  impulse  or  hormone,  it  does  so  by  causing  a  change  in 


PHYSIOLOGY   OF   THE  DIGESTIVE   GLANDS  421 

the  permeability  of  the  lumen  border  of  the  cell.  This  change  in  permea- 
bility may  be  dependent  upon  alterations  in  surface  tension  brought 
about  by  the  migration  of  electrolytes  to  the  border.  That  such  a  migra- 
tion of  electrolytes  does  actually  occur  has  been  demonstrated  by  A.  B. 
Macallum8  who  developed  a  microchemical  test  for  potassium,  and  was 
able  to  show  that  this  electrolyte  accumulates  at  the  lumen  border  of  the 
cell  during  secretory  activity.  Potassium  may  be  taken  as  a  prototype 
of  electrolytes  in  general.  Support  is  given  to  this  view  by  the  fact 
that  potassium  always  accumulates  at  the  border  of  the  cell  through 
which  the  secretion  takes  place.  In  the  epithelium  of  the  small  intes- 
tine, for  instance,  where  the  current  goes  in  the  opposite  direction  to  that 
in  gland  cells,  the  accumulation  of  potassium  occurs  at  the  portion  of 
the  cell  next  the  basement  membrane. 

Another  possibility  is  that,  when  the  gland  becomes  more  active,  the 
molecules  present  in  the  cell  become  broken  down  into  smaller  molecules 
and  so  raise  the  osmotic  pressure  of  the  cell  content,  with  the  result  that 
water  is  attracted  from  the  blood. 

When  the  gland  is  excited  so  that  the  zymogen  granules,  as  well  as 
water  and  salts,  are  secreted,  the  primary  change  appears  to  involve  the 
granules  only.  Those  near  the  lumen  swell  up  by  absorbing  water,  and 
become  converted  into  spheres  in  which  salts  are  dissolved  in  smaller 
proportions  than  exist  in  the  lymph  bathing  the  cells.  These  swollen 
structures  are  then  ruptured  at  the  periphery  of  the  cell  and  discharged 
into  the  lumen.  This  discharge  of  a  fluid  containing  fewer  saline  con- 
stituents than  the  cell  or  surrounding  blood  plasma  brings  about  in- 
creased concentration  in  the  remaining  parts  of  the  cell,  a  process  which 
possibly  is  assisted  by  a  breaking  up  of  molecules  in  the  protoplasm  itself, 
and  which  causes  an  increase  in  osmotic  pressure  with  a  consequent 
flow  of  water  from  the  lymph  to  the  cells  and  therefore  from  the  blood 
to  the  lymph. 

OTHER  CHANGES  DURING  ACTIVITY 

Whatever  may  be  the  nature  of  the  physiological  changes  that 
are  responsible  for  the  secretory  activity  of  the  cell,  the  fact  stands  out 
prominently  that  a  considerable  expenditure  of  energy  is  entailed.  This 
is  indicated  by  the  fact  that  considerably  larger  quantities  of  oxygen 
are  taken  up  by  the  gland  when  it  is  in  an  active  state  than  when  at 
rest.  Thus,  the  oxygen  consumption  of  the  resting  submaxillary  gland 
of  the  cat  may  be  increased  five  times  during  active  secretion.  On 
account  of  this  increased  oxygen  consumption  it  is  not  surprising  that 
it  should  be  found  that  the  secretory  activity  of  the  cell  is  greatly  im- 
paired by  a  deficiency  in  oxygen. 


422  DIGESTION 

These  active  processes  occurring  in  the  gland  when  it  is  excited  to 
secrete  are  associated  with  changes  in  electric  reaction  and  in  the 
volume  of  the  gland.  The  electric  changes  have  been  most  extensively 
studied  in  connection  with  the  salivary  gland.  Cannon  and  Cattel,6  by 
connecting  a  galvanometer  with  nonpolarizable  electrodes,  one  placed 
on  the  gland  and  the  other  on  neighboring  connective  tissue,  were  able 
to  show  that  with  each  period  of  active  secretion  a  current  of  action  was 
set  up.  This  was  first  discovered  by  Rose  Bradford  and  Bayliss,  and 
has  been  carefully  studied  by  Gesell.'ia  That  the  electric  current  is 
definitely  associated  with  the  secretion  of  saliva  and  is  not  caused  by 
the  vascular  changes  which  usually  accompany  this  act  was  shown  by 
its  occurrence  when  the  blood  supply  was  shut  off  from  the  gland, 
and  by  its  absence  when  there  was  no  secretion  even  though  the  vascular 
changes  were  brought  about ;  neither  is  the  electric  change  due  to  the 
movement  of  fluid  along  the  duet,  as  evidenced  by  its  persistence  after 
ligation  of  the  duct. 

With  regard  to  change  in  volume,  it  might  be  expected,  on  account  of 
the  greater  vascularity  of  the  gland  accompanying  activity,  that  this 
would  increase.  On  the  contrary,  however,  it  has  been  shown  to  de- 
crease, because  of  the  large  quantity  of  fluid  secreted  from  the  gland  cells. 

The  action  of  two  drugs  on  the  gland  cells  is  of  considerable  physio- 
logic importance:  that  of  atropine,  which  paralyzes  the  secretion,  and 
that  of  pilocarpine,  which  stimulates  it.  We  shall  see  later  how  this 
information  may  be  used  in  working  out  the  exact  mechanism  of  the 
different  glands. 

Important  observations  concerning  the  relationship  of  glandular  activ- 
ity to  the  blood  supply  have  been  made  by  experiments  in  which  glands 
were  artificially  perfused  outside  the  body.  When  the  submaxillary 
gland  of  the  dog  is  perfused  with  oxygenated  Ringer's  solution,  stimula- 
tion of  its  nerve  supply  does  not  produce  the  usual  secretion,  but  if  the 
Ringer's  solution  is  mixed  with  blood  plasma,  the  nerve  stimulation  has  its 
usual  effect  for  a  short  time.  Although  no  secretion  occurs  when 
oxygenated  Ringer's  solution  is  perfused  alone,  the  usual  vascular 
changes  still  occur  in  the  gland.  The  results  seem  to  indicate  that  the 
presence  of  some  constituent  of  the  blood  plasma  is  essential  for  the 
change  in  the  permeability  of  the  cell  wall  necessary  for  the  process  of 
secretion.  Similar  results  have  been  obtained  during  artificial  perfusion 
of  the  pancreas  when  secretin  was  used  as  the  stimulus. 

CONTROL  OF  GLANDULAR  ACTIVITY 

Having  outlined  the  general  nature  of  the  changes  occurring  in  gland 
cells  during  their  activity,  Ave  may  now  proceed  to  study  the  nature  of 


Center  for 

cranial  secretory  fibers 


Center  for  'iw^jgig 
vasodilator  nerves- 


Facial  nervejvVJ///). 
Cerebellum^x^ 
Glossopharyngeal,  nerve 

Medulla  oblongata 
Parotid  gland 


Otic  ganglion 
Semilunar {Casserian)  ganglion 
'Chorda  tympani  nerve_^=z^ 
Small  superficial  ^^^ 
petrosal  nerve '^y<Parotid  duct 
Inf.max.div.N.V^       (Stenson's) 

Submaxillary 
duct  (Wharton's) 

■Sublingual 
duct 

(Bartholin's) 
Ungual  nerve 
Chordo-lingual 

triangle 


Electrodes' 
/(Small  amount  of  thick  saliva 
vasoconstriction  ) 

Vaso  constrictor  fibers 
sympathetic  secretory  fibers 

^Outgoing  sympathetic 
rami  communicantes 


Electrodes 
( Large  amount  of  thin 
saliva, 
vasodilatation 

Sublingual  gland 


Post  ganglionic  fibers  are 
dotted  thus  -— 


Fig.    145.  —Diagrammatic   representation   of  the  innervation  of  the  salivary   glani 

Jackson.) 


in   the   dog.      (From 


PHYSIOLOGT   OP   THE   DIGESTIVE   GLANDS  123 

the  process  by  which  this  glandular  activity  is  controlled.  Two  mechan- 
isms of  control  arc  known:  (1)  by  the  nervous  system,  and  (2)  by  means 
of  hormones. 

Nervous  Control. — Control  through  the  nervous  system  is  most  marked 
— indeed  it  may  be  the  only  means  of  control — in  glands  which  have  to 
produce  their  secretion  promptly,  whereas  hormone  control  pre- 
dominates in  those  in  which  prompt  changes  in  secretory  activity  are  not 
required.  Thus,  nervous  control  alone  is  present  in  the  salivary  glands, 
whereas  hormone  control  is  predominant  in  the  pancreas,  intestinal 
glands  and  liver.  The  gastric  glands  are  partly  under  nervous  control, 
and  partly  under  hormone  control.  It  should  be  pointed  out  here  that 
the  glands  of  the  body  other  than  the  digestive  glands  are  also  subject  to 
nervous  or  hormone  control  according  to  the  promptness  with  which  they 
are  required  to  secrete.  The  lachrymal  and  sweat  glands,  and  the  venom 
glands  of  reptiles,  for  example,  are  practically  entirely  under  nervous 
control,  whereas  most  of  the  ductless  glands,  with  the  exception  of  the 
adrenals,  are  mainly  under  the  influence  of  hormones. 

The  exact  nature  of  the  nervous  control  of  glandular  function  has, 
therefore,  been  most  extensively  studied  in  the  salivary  glands,  and  that 
of  the  hormonic  in  the  pancreas.  With  regard  to  the  salivary  glands, 
the  following  points  are  of  importance:  Their  nerve  supply  comes  from 
two  sources:  the  cerebral  autonomic,  and  the  sympathetic  autonomic 
(see  page  877).  These  two  nerve  supplies  have  usually  an  opposite  influ- 
ence on  the  secretory  activity  of  the  glands,  and  very  frequently  also  on 
the  vascular  changes  that  accompany  secretory  activity. 

On  account  of  its  ready  accessibility,  the  submaxillary  gland  in  the 
dog  and  cat  has  been  most  thoroughly  investigated.  The  cerebral  auto- 
nomic nerve  in  this  case  is  represented  by  the  chorda  tympani,  and  the 
sympathetic  autonomic  by  postganglionic  fibers  that  run  from  the 
superior  cervical  ganglion  to  the  gland  along  its  blood  vessels  (Fig.  145). 
After  tying  a  cannula  into  the  duct  of  the  gland,  it  will  be  found  in  the 
dog  that  stimulation  of  the  chorda  tympani  produces  an  immediate  and 
abundant  secretion  of  thin  watery  saliva  accompanied  by  a  marked 
dilatation  of  the  blood  vessels  of  the  gland. 

That  this  secretion  is  not  dependent  on  the  vasodilatation  is  easily 
shown  by  repeating  the  experiment  after  administering  a  sufficient  dose 
of  atropine  to  paralyze  the  secreting  cells.  Stimulation  of  the  nerve  then 
produces  a  vasodilatation  but  no  secretion.  The  same  conclusion  is 
arrived  at  by  an  experiment  of  an  entirely  different  nature ;  namely,  by 
observing  the  pressure  produced  in  the  duet  when  the  chorda  tympani  is 
stimulated.  This  pressure  rises  considerably  above  that  in  the  arteries, 
so  that  no  such  physical  process  as  mere  diffusion  can  be  held  accountable 


424  DIGESTION 

for  the  secretion,  and  therefore  vasodilatation  alone  can  not  be  respon- 
sible for  it.  If  the  sympathetic  nerve  supply  is  stimulated,  a  very  scanty, 
thick  secretion  takes  place  accompanied  by  vasoconstriction. 

Eepetition  of  these  experiments  in  the  cat  yields  different  results, 
particularly  with  regard  to  the  influence  of  the  sympathetic,  a  copious 
secretion  being  produced  by  such  stimulation.  The  histologic  changes 
produced  in  the  gland  cells  are  marked  after  sympathetic  stimulation, 
but  very  slight,  if  present  at  all,  after  chorda  stimulation. 

The  outstanding  conclusion  which  may  be  drawn  from  these  results 
is  that  two  kinds  of  secretory  activity  are  mediated  through  the  nerves; 
one  causing  a  thin  watery  secretion,  containing  only  a  small  percentage 
of  organic  matter,  and  the  other,  a  thick  viscid  secretion  with  a  large 
amount  of  organic  material.  To  explain  these  differences  the  hypothe- 
sis has  been  advanced  that  there  are  really  two  kinds  of  secretory 
fibers,  called  secretory  and  trophic,  the  former  having  to  do  with  the 
secretion  of  water  and  inorganic  salts,  and  the  latter  with  the  secretion 
of  organic  matter ;  i.  e.,  with  the  extrusion  of  the  zymogen  granules. 
Certain  authors  (Langley)  believe  that  such  an  hypothesis  is  unneces- 
sary, and  that  the  different  results  are  dependent  upon  the  concomitant 
changes  in  the  blood  supply  produced  by  stimulating  one  or  other  nerve. 

That  there  are  really  different  kinds  of  true  secretory  fibers  is,  however, 
evident  from  the  following  experiment.  If  the  duct  of  the  gland  is 
made  to  open  through  a  fistula  in  the  cheek,  secretion  of  saliva  through 
the  fistula  can  be  induced  by  placing  various  substances  in  the  mouth,  such 
as  meat  powder  or  hydrochloric  acid.  If  the  experiment  is  performed  in 
such  a  way  that  the  bloodfloAv  through  the  gland  can  be  observed,  it  will 
be  found  that  the  saliva  produced  by  the  stimulation  with  the  meat  powder 
contains  a  very  much  higher  percentage  of  organic  material  than  does  that 
produced  when  hydrochloric  acid  is  the  stimulant,  whereas  the  vascular 
changes  in  the  gland  and  the  inorganic  constituents  of  the  saliva  are  the 
same  in  both  cases.  Since  stimulation  of  the  chorda  tympani  causes  the 
secretion  of  a  watery  saliva,  while  that  caused  by  stimulation  of  the 
sympathetic  is  thick,  it  might  be  thought  that  the  secretory  fibers  were 
contained  in  the  former  and  the  trophic  fibers  in  the  latter  nerve ;  that 
this  is  not  the  case  can  be  shown  by  a  repetition  of  the  above  experiment 
in  animals  from  which  the  superior  cervical  ganglion  has  been  removed. 
The  same  results  are  obtained,  indicating  that  the  chorda  tympani  con- 
tains both  secretory  and  trophic  fibers. 


CHAPTER  XL1X 
PHYSIOLOGY  OF  THE  DIGESTIVE  GLANDS  (Cont'd) 

THE  HORMONE  CONTROL 

This  is  exhibited  best  in  the  case  of  the  pancreas.  The  crucial  experi- 
ment demonstrating  that  this  gland  is  not  primarily  dependent  upon 
nervous  impulses  for  the  control  of  its  activity  was  performed  by  Bay- 
liss  and  Starling.2  Starting  with  the  well-known  fact  that  the  application 
of  weak  acid  to  the  duodenal  mucous  membrane  excites  secretion  of  pan- 
creatic juice,  these  workers  carefully  severed  all  the  nerve  connections  of 
a  portion  of  the  duodenum,  and  found  on  again  applying  acid  to  the  mucous 
membrane  that  the  secretion  persisted.  To  explain  this  result  they  postu- 
lated that  the  acid  must  cause  some  substance  to  be  liberated  into  the 
blood  stream,  which  carries  it  to  the  pancreas,  the  cells  of  which  it  then 
excites  to  activity.  To  test  this  hypothesis  they  scraped  off  the  mucous 
membrane  of  the  duodenum  and  ground  it  in  a  mortar  with  weak  hydro- 
chloric acid  (0.6  per  cent),  and,  after  boiling  the  solution  so  as  to  remove 
the  protein  and  nearly  neutralizing  it,  they  obtained  a  fluid  which,  when 
injected  intravenously,  immediately  caused  a  copious  secretion  of  pan- 
creatic juice. 

Accompanying  the  secretion,  however,  a  marked  fall  in  arterial  blood 
pressure  was  observed,  making  it  possible  that  the  secretion  might  have 
been  due  to  a  vasodilatation  occurring  in  the  pancreatic  blood  vessels.  To 
eliminate  this  possibility  they  prepared  an  extract  that  was  free  of  the 
depressor  substances  by  extracting  intestinal  epithelium  without  any  of  the 
submucous  tissue.  The  resulting  extract  had  merely  the  secretory  effect 
and  produced  no  fall  in  blood  pressure.  This  secretagoguary  substance 
they  named  secretin. 

Further  evidence  that  the  action  of  secretin  is  independent  of  the 
depressor  substances  has  been  obtained  by  taking  advantage  of  the  fact 
that  the  depressor  substance  is  more  soluble  in  alcohol  than  the  secretin. 
If  an  acid  decoction  of  duodenal  mucous  membrane  is  poured  into  abso- 
lute alcohol,  a  precipitate  is  formed.  If  this  precipitate  is  redissolved 
in  water  and  reprecipitated  several  times  by  absolute  alcohol,  then  after 
drying  a  white  poAvder  is  obtained,  which  is  easily  soluble  in  water.  The 
resulting  solution  injected  intravenously  has  a  powerful  secretory  action, 
but  produces  no  effect  on  blood  pressure.     The  concentrated  alcoholic 

425 


426  DIGESTION 

liquor,  on  the  other  hand,  when  similarly  injected  produces  a  marked  fall 
in  blood  pressure.  It  is  believed  that  this  effect  is  due  to  the  action  of 
/Mniidazolylethylamine.  A  very  strong  preparation  of  secretin  can  also 
be  prepared  by  the  method  of  Dale  and  Laidlaw,7  which  depends  on  pre- 
cipitation by  mercuric  chloride. 

Secretin  does  not  exist  preformed  in  the  epithelial  cells,  as  is  shown  by 
the  fact  that  an  extract,  made  with  neutral  saline  solution,  does  not  as  a 
rule,  have  any  secretory  action  when  injected  intravenously.  Sometimes 
a  slight  secretion  may  be  produced,  but  this  is  probably  to  be  explained 
by  the  fact  that  some  secretin  remains  behind  in  the  cells  as  a  result  of  a 
preceding  phase  of  activity.  If,  on  the  other  hand,  the  above  neutral  or 
slightly  alkaline  opalescent  solution  of  the  mucous  membrane  is  boiled 
with  acid,  secretin  may  become  developed  in  it.  The  interpretation  put 
upon  these  results  is  that  a  substance,  called  prosecretin,  exists  in  the 
epithelial  cells,  and  that  this  becomes  converted  into  secretin  by  the  action 
of  acid  on  the  cells.  The  secretin  thus  produced  is  then  taken  up  by  the 
blood,  none  of  it  passing  into  the  intestinal  canal,  because  the  free  borders 
of  the  cells  are  impervious  to  secretin.  That  this  is  actually  the  case  has 
been  shown  by  finding  that  the  introduction  of  neutralized  secretin  solu- 
tion into  the  duodenum,  or  other  parts  of  the  small  intestine,  does  not 
cause  a  secretion  of  pancreatic  juice. 

We  know  practically  nothing  concerning  the  chemical  nature  of  secretin. 
Being  soluble  in  about  90  per  cent  alcohol  and  in  fairly  weak  acids,  it  can 
not  belong  to  any  of  the  better  known  groups  of  proteins.  As  it  is 
readily  diffusible  through  parchment  membrane,  it  can  not  be  of  very 
complex  structure,  and  as  it  withstands  heat,  it  can  not  be  an  enzyme. 
It  rapidly  deteriorates  in  strength  in  the  presence  of  alkalies. 

Any  acid  when  applied  to  the  mucous  membrane  is  capable  of  producing 
secretin,  and  so  are  certain  other  substances,  such  as  mustard  oil.  "Watery 
solutions  of  saccharose  or  urea,  when  rubbed  up  with  the  duodenal  mucosa 
in  a  mortar,  produce  secretin  solutions  of  varying  activity,  but  they  do 
not  in  the  living  animal  excite  pancreatic  secretion  when  applied  to  the 
duodenum.  Secretin  is  very  susceptible  to  destruction  by  such  digestive 
enzymes  as  those  present  in  the  pancreatic,  gastric,  and  intestinal  juices. 
That  secretin  is  present  in  the  blood  when  acid  is  in  contact  with  the 
duodenal  mucosa  has  been  shown  by  the  fact  that  injection  into  a  normal 
dog  of  blood  from  one  in  which  secretin  formation  is  going  on  (as  a 
result  of  acid  in  the  duodenum),  excites  pancreatic  secretion. 

The  pancreatic  juice  produced  by  the  injection  of  secretin,  like  that 
which  is  produced  under  normal  conditions,  does  not  contain  any  active 
trypsin,  but  instead  contains  its  precursor,  trypsinogen.  This  becomes 
converted  into  trypsin  in  the  intestine,  being  activated  by  contact  with 


PHYSIOLOGY    OK    Til  10    DKilOSTIVE    GLANDS 


427 


enterokinase,  an  enzyme  present  in  the  intestinal  juice.    By  such  a  mechan- 
ism the  mucosa  of  the  pancreatic  duct  is  protected  against  autodigestion 

by  trypsin. 

NERVOUS  CONTROL  OF  PANCREAS 

Trior  to  the  discovery  of  secretin,  Pavlov1  and  his  pupils  had  published 
numerous  experiments  purporting'  to  show  that  the  secretion  of  pancreatic 


6     * 


@hm 

•& 

if 

x* ' 

!'•"*•  ^*^L'      " 

"jj»  I '■' 

&$ 

4P  wQss 

Fig.  146. — Pancreatic  acini  stained  with  hematoxylin.  The  acini  at  the  top  and  to  the  left 
of  the  figure  are  from  a  resting  gland,  those  to  the  right  being  from  one  that  had  been  secreting 
for  over  three  hours  as  a  result  of  acid  in  the  duodenum.  The  lowermost  figure  is  from  a  gland 
the  vagus  nerve  supply  of  which  had  been  stimulated  off  and  on  for  several  hours.  Note  that 
the  zymogen  granules  are  extruded  only  after  vagus  activity  but  not  after  secretin  activity.  (From 
Babkin,  Rubaschkin  and  Ssawitsch.) 

juice  is  controlled  through  the  vagus  nerve.  The  amount  of  secretion 
produced  by  nervous  stimulation  was,  however,  never  found  to  be  so  large 
as  that  produced  by  secretin,  and  for  several  years  after  the  discovery  of 


428 


DIGESTION 


the  latter  hormone,  much  doubt  existed  as  to  the  correctness  of  Pavlov's 
claim.  As  in  many  other  fields  of  physiologic  science,  investigators  at- 
tempted to  show  that  one  or  the  other  mechanism  obtained,  and  they  were 
not  inclined  to  consider  the  possibility  that  both  mechanisms  might  exist 
side  by  side.  That  such  is  the  case,  however,  is  clear  from  the  most  recent 
work,  in  which  it  has  been  found  that  if  proper  precautions  are  taken, 
repeated  stimulation  of  the  vagus  nerve  does  call  forth  a  secretion  of 
pancreatic  juice  which,  besides  being  less  copious  than  that  following 


m 


ii. 


in. 


Fig.  147. — Three  preparations  of  pancreatic  acini  stained  by  eosin  orange  toluidin  blue.  The 
acini  of  Fig.  I  were  from  a  gland  after  vagus  stimulation,  and  it  is  noted  that  besides  free  ex- 
trusion of  the  granules,  globules  staining  with  orange  (and  appearing  in  deep  black  in  the  photo- 
graph) have  formed  and  may  be  present  in  the  ductules.  Some  of  the  globules,  however,  change 
in  their  staining  properties,  becoming  light  red  (dark  gray  in  photograph).  The  acini  in  II  and  III 
were  from  glands  excited  by  secretin.  No  globules  appear;  the  granules  remain,  and  fine  canaliculi 
appear  in   the   clear  protoplasm.      (From   Babkin,    Rubaschkin   and   Ssawitsch.) 


secretin  injection,  differs  from  it  in  the  important  fact  that  it  contains 
not  trypsinogen  but  active  trypsin.  Since  the  normal  pancreatic  juice 
contains  trypsinogen,  this  last  mentioned  fact  would  appear  to  indicate 
that  vagus  control  of  the  normal  secretion  can  not  be  an  important  affair. 
The  vagus  secretion  of  pancreatic  juice  is,  moreover,  paralyzed  by  atro- 
pine, which  has  no  action  on  the  secretin  mechanism  (cf.  Bayliss). 


PHYSIOLOGY   OF    THE    DIGESTIVE   GLANDS  429 

The  copious  secretion  of  pancreatic  juice  produced  by  secretin,  on  the 
one  hand,  and  the  scanty,  thick  secretion  produced  by  vagus  stimula- 
tion, on  the  other,  calls  to  mind  similar  differences  observed  in  the  secre- 
tion of  saliva  as  the  result  of  chorda-tympani  or  sympathetic  stimulation. 
It  will  be  remembered  that  from  these  latter  results  it  was  concluded 
that  there  must  be  secretory  and  trophic  fibers  concerned  in  the  control 
of  the  activities  of  gland  cells.  Interesting  corroboration  of  this  conclusion 
has  recently  been  obtained  by  histologic  examination  of  the  pancreas  fol- 
lowing secretin  or  vagus  activity.  After  the  repeated  injection  of  secre- 
tin, it  is  difficult  to  observe  any  signs  of  fatigue  in  the  cells ;  the  zymogen 
granules  remain  practically  as  numerous  as  in  a  resting  gland,  but  in  the 
clear  protoplasm  of  the  outer  third  of  the  cell,  it  is  said  that  fine  channels 
of  fluid  can  be  seen.  Through  these  channels  water  is  believed  to  pass 
from  the  blood  towards  the  lumen  and  in  its  course  to  carry  with  it  some 
of  the  zymogen  granules,  without,  however,  changing  them.  Thus,  when 
the  gland  cells  are  stained  with  eosin  and  orange,  after  secretin  activity 
some  of  the  zymogen  granules  can  occasionally  be  seen!  in  the  lumen  of 
the  acini  stained  with  eosin  like  those  in  the  cell  itself.  After  vagus 
stimulation  the  appearances  are  different ;  not  only  are  the  granules  more 
freely  extruded  from  the  cells,  but  they  undergo  a  preliminary  change; 
they  lose  the  property  of  staining  with  eosin  and  become  stained  with 
the  orange,  at  the  same  time  increasing  in  size  so  as  to  form  vacuoles. 
These  vacuoles  may  wander  into  the  ductules,  and  when  they  are  present 
here  they  are  stained  by  orange  (Figs.  146  and  147)  (Babkin,  etc.7a). 

Why  there  should  be  both  a  nervous  and  a  hormone  control  of  the  pan- 
creatic secretion  is  not  clear.  This  gland,  unlike  the  gastric  and  salivary 
glands,  is  not  called  upon  to  become  active  all  of  a  sudden,  and  it  is  dif- 
ficult to  see  what  could  serve  as  the  normal  stimulus  operating  through 
the  nervous  pathway.  Taking  it  all  in  all,  it  is  probably  safe  to  con- 
clude that  the  nervous  mechanism  is  relatively  unimportant,  and  that 
under  normal  conditions  it  seldom  if  ever  is  called  into  operation.  Cor- 
roboration for  this  view  is  afforded  by  the  fact,  above  mentioned,  that 
the  pancreatic  juice  produced  by  vagus  stimulation  contains  active  tryp- 
sin, which  is  not  the  case  with  normal  pancreatic  juice. 


CHAPTER  L 

PHYSIOLOGY  OF  THE  DIGESTIVE  GLANDS  (Cont'd) 

Up  to  the  present  we  have  been  concerned  with  the  physiologic  activi- 
ties of  digestive  glands  in  general,  but  now  we  must  study  each  of  them 
separately  in  order  to  find  out  the  conditions  under  which  they  become 
stimulated  to  activity  in  the  normal  process  of  digestion.  The  secretion 
of  each  gland  has  a  definite  role  assigned  to  it  in  the  complex  and  lengthy 
process  of  digestion.  It  takes  up  its  work  where  the  preceding  secre- 
tion left  off;  e.g.,  the  pepsin  of  gastric  juice  digests  protein  so  far  as 
proteoses  and  peptone ;  the  trypsin  of  pancreatic  juice  then  attacks  the 
proteoses  and  peptone,  and  the  resulting  lower  degradation  products 
are  finally  attacked  by  the  erepsin  of  the  intestinal  juice.  The  secre- 
tions of  the  various  glands  are,  therefore,  required  in  a  certain  definite 
order — they  are  correlated;  and  we  must  now  give  some  attention  to  the 
precise  condition  upon  which  the  activity  and  correlation  depend. 

THE   NORMAL   CONDITIONS   UNDER   WHICH   THE    GLANDS 
BECOME  STIMULATED  TO  INCREASED  ACTIVITY 

To  make  possible  such  observations  on  the  normal  activities  of  the 
glands,  a  preliminary  operation  has  to  be  performed  so  as  to  bring  the 
duct  of  the  gland  to  the  surface  of  the  bod}'  and  permit  of  the  observa- 
tion of  its  secretory  activity  after  the  animal  has  recovered  from  the 
immediate  effects  of  the  operation.  We  owe  to  Pavlov1  the  surgical 
technic  by  which  these  conditions  can  be  fulfilled.  The  general  principle 
of  the  operation,  in  the  case  of  glands  provided  with  duets,  consists  in 
making  a  circular  cut  through  the  mucous  membrane  surrounding  the 
opening  of  the  duct  and  then,  after  dissecting  the  duct  free,  stitching 
the  edges  of  the  cut  to  the  skin  wound.  Healing  then  takes  place  without 
the  formation  in  the  duet  of  any  stricture  due  to  the  cicatricial  tissue.  After 
the  wound  has  healed,  the  secretion  can  readily  be  collected  in  a  receiver 
attached  over  the  duct  fistula,  the  animal  being  in  every  other  way  in  a 
perfectly  normal  condition.  In  the  case  of  glands  not  provided  with  a 
duct,  other  methods  must  be  adopted  to  collect  the  secretions.  These 
will  be  described  elsewhere. 

430 


PHYSIOLOGY   OP   Till;   DIGESTIVE   GLANDS  431 

THE  NORMAL  SECRETION  OF  SALIVA 

The  duct  fistula  can  in  this  case  be  made  cither  for  the  submaxillary 
gland,  representing  a  mucous  gland,  or  for  the  parotid,  representing  a 
serous  gland.  Under  ordinary  conditions  there  is  very  little  secretion 
from  either  duct.  When  secretion  occurs,  it  is,  of  course,  caused  by 
influences  acting  on  a  nerve  center  or  centers  in  the  medulla  oblongata, 
the  exact  location  of  which  for  the  different  glands  has  been  worked  out 
in  recent  years  by  Miller.9  The  impulses  acting  on  these  centers  may  be 
transmitted  along  afferent  nerves  coming  from  the  mucous  membrane  of 
the  mouth,  nares,  etc.,  or  by  impulses  which  we  may  call  psychic,  trans- 
mitted from  the  higher  nerve  centers.  The  reflex  secretions  caused  by 
impulses  traveling  by  the  afferent  nerve  from  the  mouth,  etc.,  have  been 
called  unconditioned,  and  those  from  the  higher  nerve  centers,  condi- 
tioned. With  regard  to  the  former,  there  is  considerable  discrimination 
in  the  type  of  stimulus  that  will  be  effective.  Thus,  if  the  dog — for  most 
of  the  experiments  have  been  performed  on  this  animal — is  given  meat, 
a  secretion  of  thick,  mucous  saliva  will  be  observed  to  occur  (submaxil- 
lary gland).  On  the  other  hand,  if  the  meat  is  dried  and  pulverized, 
the  secretion  which  it  calls  forth  will  be  very  copious  and  watery  (par- 
otid gland).  There  is,  then,  an  obvious  association  between  the  nature 
of  the  secretion  and  the  function  it  will  be  called  upon  to  perform  when 
it  becomes  mixed  with  the  food.  The  mucous  secretion  called  forth  by 
meat  will  serve  to  lubricate  the  bolus  of  food  and  thus  facilitate  its 
swallowing,  whereas  the  thin  watery  secretion  produced  by  the  dry 
powder  will  have  the  effect  of  washing  the  powder  from  the  mouth. 

It  is  evident  that  the  mechanical  condition  of  the  food  partly  deter- 
mines its  exciting  quality.  Mechanical  stimulation  of  the  mucosa  alone  is, 
however,  not  an  adequate  stimulus,  for  if  pebbles  are  placed  in  the  mouth, 
little  secretion  occurs,  but  if  sand  is  placed  in  the  mouth,  secretion  immedi- 
ately becomes  copious.  The  nerve  endings  also  respond  to  chemical  stimuli. 
Thus,  weak  acid  causes  a  copious  secretion,  while  alkali  has  no  effect; 
disagreeable,  nauseous  substances  also  excite  secretion.  The  above  dif- 
ferences in  the  response  of  the  glands  according  to  the  mechanical  condi- 
tion of  the  food  has  been  observed  only  in  the  ease  of  the  parotid  gland, ' 
increase  in  the  submaxillary  secretion  being  obtained  only  when  actual 
foodstuffs  are  placed  in  the  mouth. 

The  investigations  that  have  been  made  on  the  conditions  of  psychic 
secretion  of  saliva  are  still  more  interesting  and  important.  Their  im- 
portance depends  not  so  much  on  the  information  they  give  us  concern- 
ing the  secretion  of  saliva  as  such,  as  on  the  methods  they  furnish  us  for 
investigating   the    various   conditions    that    affect    the    psychic    processes 


432  DIGESTION 

associated  with  the  taking  of  food.  It  is  from  the  psychic  rather  than 
from  the  physiologic  standpoint,  therefore,  that  these  observations  are 
of  importance,  for  they  permit  us,  by  objective  methods,  to  study  on 
dumb  animals  problems  that  would  otherwise  be  beyond  our  powers  of 
investigation.  Many  of  the  results,  with  their  bearing  on  the  functions 
of  the  higher  nerve  centers,  have  been  discussed  elsewhere.  Meanwhile, 
however,  even  at  the  risk  of  repetition  it  may  not  be  out  of  place  to  cite 
a  few  of  the  most  interesting  experiments. 

If  we  tease  a  hungry  animal  with  food  for  which  he  has  a  great  appe- 
tite, a  copious  secretion  of  saliva  immediately  occurs.  If  we  go  on  teas- 
ing him  without  giving  him  food,  and  repeat  this  procedure  on  several 
succeeding  days,  it  will  be  found  that  gradually  he  no  longer  responds 
to  the  teasing  by  increased  salivation.  Evidently,  therefore,  the  reflex 
is  conditioned  upon  the  animal's  afterward  receiving  the  food. 

The  experiment  may  be  performed  in  another  way.  If,  for  example, 
we  offer  the  animal  some  food  for  which  he  has  no  appetite,  no  secre- 
tion of  saliva  will  occur;  but,  if  at  the  end  of  the  process  we  give  him 
appetizing  food,  it  will  be  found  after  repeating  this  procedure  on 
several  successive  days  that  the  presentation  of  the  unappetizing  food 
calls  forth  a  secretion.  He  has  learned  to  associate  the  presentation  of 
unappetizing  food  with  the  subsequent  gratification  of  his  appetite.  The 
experiment  can  even  be  performed  so  that  a  definite  interval  of  time 
elapses  between  the  application  of  the  stimulus  and  the  salivation:  if 
the  animal  is  teased  on  successive  days  with  food  for  which  he  has  an 
appetite  but  is  not  given  the  food  until  after  ten  or  twenty  minutes, 
presentation  of  this  food  will  come  to  be  followed  by  salivation — not 
immediately,  but  after  the  exact  interval  of  time  that  had  been  allowed 
to  intervene  in  the  training  process.  During  this  interval  there  must  be 
an  inhibition  of  psychic  stimulation  of  the  salivary  centers  by  other  nerve 
centers.  It  is  of  great  interest  that  this  inhibition  may  itself  be  inhib- 
ited by  various  forms  of  stimulation  of  the  nervous  system  (see  page  858). 

THE  SECRETION  OF  GASTRIC  JUICE 

Methods  of  Investigation 

There  being  no  common  duct,  the  secretion  of  the  gastric  glands  is  a 
much  more  difficult  problem  to  investigate  than  is  that  of  glands  which, 
like  the  salivary,  are  supplied  with  ducts.  One  of  the  most  interesting 
chapters  in  the  history  of  physiology  concerns  the  methods  which  from 
time  to  time  have  been  evolved  for  the  collection  of  this  juice  and  for 
studying  the  digestive  processes  in  the  stomach.  Prominent  among  the 
problems  confronting  the  earlier  investigators  was  the  question  whether 


PHYSIOLOGY   OF   THE   DIGESTIVE   GLANDS  133 

the  main  function  of  the  stomach  is  to  crush  or  triturate  the  Eood  or  to 
ad  on  it  chemically.  The  great  French  scientist  Reaumur  and  a  little 
later  the  Italian  Abbe  Spallanzani  |  L729-1799)  attacked  iliis  problem  by 

methods  that  anticipate  those  of  Rehfuss  and  Einhorn.  Spallanzani  ulti- 
mately devised  the  method  of  swallowing  small  perforated  wooden  tubes 
containing  foodstuff's  and  covered  by  small  linen  bags.  After  the  hajrs 
were  passed  per  rectum,  he  found  that  considerable  erosion  or  digestion 
of  the  food  had  occurred,  but  that  the  wooden  tubes,  however  thin- 
walled  they  might  be,  were  not  crushed.  In  order  to  secure  samples  of 
the  gastric  juice  free  from  food,  the  only  method  available  to  the  older 
investigators  consisted  in  swallowing  sponges  attached  to  threads,  which 
after  being  for  some  time  in  the  stomach  were  withdrawn  and  squeezed 
dry  of  juice. 

The  next  great  contribution  came  from  this  country,  where,  in  1833, 
Dr.  Beaumont,  while  a  surgeon  in  the  service  of  the  American  troops 
located  at  Mackinaw,  made  observations  on  a  Canadian  voyageur  by  the 
name  of  Alexis  St.  Martin,  who  by  the  premature  discharge  of  his  gun 
had  wounded  himself  in  the  stomach,  the  wound  never  healing  but  leav- 
ing a  permanent  gastric  fistula.  Beaumont  arranged  to  keep  Alexis  St. 
Martin  in  his  service  for  several  years,  during  which  time  he  made 
numerous  observations  on.  the  process  of  digestion  in  the  stomach — 
observations  many  of  which  are  of  great  value  even  at  the  present  day. 

By  none  of  these  methods,  however,  could  a  sample  of  pure  gastric 
juice  be  secured  while  the  digestive  process  was  actually  in  progress. 
To  make  the  collection  .of  such  a  sample  possible,  Heidenhain  devised  a 
method  of  isolating  portions  of  the  stomach  wall  as  pouches  opening 
through  fistulas  on  the  abdominal  wall.  The  results  of  Heidenhain 's 
experiments  are,  however  open  to  the  objection  that  the  secretion  in 
the  isolated  pouches  may  not  really  correspond  to  that  occurring  in  the 
main  stomach,  since  the  connections  of  the  pouches  with  the  central 
nervous  system  must  have  been  severed.  In  order  that  these  connec- 
tions might  remain  as  nearly  intact  as  possible,  the  Russian  physiologist, 
Pavlov,1  devised  an  ingenious  operation  in  which  the  pouch,  or  "minia- 
ture stomach,"  remains  connected  Avith  the  main  stomach  through  a  con- 
siderable width  of  mucous  and  submucous  tissue.  The  essential  nature 
of  this  operation  will  be  evident  from  the  accompanying  diagram. 
(Fig.  148). 

The  most  recent  investigations  have  been  made  by  Cannon3  and  by 
Carlson.4  The  former  fed  animals  food  impregnated  with  bismuth  sub- 
nitrate,  and  then  exposed  the  animal  to  the  x-rays.  A  shadow  is 
produced  by  the  food  mass  in  the  stomach,  and  from  the  changes  in  the 
outline  of  this  shadow  facts  have  been  collected,  not  only  concerning  the 


434 


DIGESTION 


movements  of  the  viscus,  but  also  concerning  the  rate  of  discharge  of 
food  into  the  intestine  and  therefore  the  duration  of  the  gastric  digestive 
process.  Carlson's  contribution  has  been  rendered  possible  by  his  good 
fortune  in  having  in  his  service  a  second  Alexis  St.  Martin,  a  man  with 
complete  closure  of  the  esophagus  and  a  gastric  fistula  large  enough  to 
permit  of  direct  inspection  of  the  interior  of  the  stomach.  Seizing  the 
opportunity  thus  presented,  Carlson  during  the  last  four  or  five  years 
has  devoted  his  attention  exclusively  to  a  thorough  investigation,  not 
only  of  the  movements  of  the  stomach,  but  also  of  the  rate  of  secretion 
of  the  gastric  juice  under  different  conditions.  He  has  also,  with  praise- 
worthy enthusiasm  and  keen  scientific  spirit,  extended  his  observations 
both  on  laboratory  animals  and  on  himself  and  his  coworkers,  so  as  not 


A*» 


Fig.  148. — Diagram  of  stomach  showing  miniature  stomach  (5)  separated  from  the  main  stomach 
(I  )  by  a  double  layer  of  mucous  membrane.  A. A.,  is  the  opening  of  the  pouch  on  the  abdominal 
wall.      (Pavlov.) 

to  incur  the  error,  which  is  all  too  frequently  made,  of  confining  the 
observations  to  one  animal. 


The  Nervous  Element  in  Gastric  Secretion 

The  first  stimulus  to  the  secretion  of  gastric  juice  is  nervous  in  origin, 
and  is  dependent  on  the  gratification  of  the  appetite  and  the  pleasure  of 
taking  food.  This  fact,  after  having  been  suggested  by  observations 
made  in  the  clinic,  was  first  thoroughly  investigated  by  Pavlov,  who  for 
this  purpose  observed  the  gastric  secretion  flowing  either  from  a  fistula 
of  the  stomach  itself,  or  from  a  "miniature  stomach,"  in  dogs  in  which 
also  an  esophageal  fistula  had  been  established.  When  food  was  given 
by  mouth  to  these  animals,  it  was  chewed  and  swallowed  in  the  usual 
manner,  but  before  reaching  the  stomach,  it  escaped  through  the  esopha- 


PHYSIOLOGY   OP   THE   DIGESTIVE   GLANDS  435 

•_rc.il  fistula.  This  experiment  is  known  as  that  of  "sham  feeding." 
Within  a  few  minutes  after  giving  food  the  gastric  juice  was  found  to 
be  secreted  actively,  and  if  the  feeding  process  was  kept  up,  which  could 
be  done  almost  indefinitely  since  the  animal  never  became  satisfied,  the 
secretion  continued  to  flow.  Thus,  in  one  instance  Pavlov  succeeded  in 
collecting  about  700  c.c.  of  gastric  juice  after  sham  feeding  an  animal 
for  five  or  six  hours  in  the  manner  above  described. 

After  the  stomach  has  emptied  itself  of  the  food  taken  with  the  pre- 
vious meal,  it  is  said  by  Pavlov  to  contain  only  a  little  alkaline  mucus. 
The  more  recent  work  of  Carlson,  however,  shows  that  this  is  not  strictly 
the  case,  there  being  more  or  less  of  a  continuous  secretion  of  gastric  juice 
in  the  entire  absence  of  food.  The  amount  varies  from  a  few  c.c.  up  to 
60  c.c.  per  hour,  more  secretion  being  produced  when  it  is  collected  every 
five  or  ten  minutes  than  if  it  is  collected  every  thirty  or  sixty,  thus 
indicating  that,  ordinarily,  some  escapes  through  the  pylorus  into  the 
duodenum.  The  secretion  contains  both  pepsin  and  hydrochloric  acid. 
As  to  the  cause  of  this  continuous  secretion,  little  is  known.  It  may  be 
an  example  of  the  periodic  activities  of  the  digestive  glands  described  by 
Boldyreff,  or  it  may  in  part  be  due  to  a  psychic  stimulation  dependent 
upon  the  thought  of  food.  That  the  latter  is  probably  not  the  cause,  is 
indicated  by  the  fact  that,  at  least  in  Carlson's  patient,  the  psychic  juice 
could  not  be  made  to  flow  short  of  giving  food. 

The  sham  feeding  causes  stimulation  of  the  gastric  secretion  through 
impulses  transmitted  to  the  stomach  along  the  vagus  nerves;  for  it  has 
been  found,  in  animals  in  which  the  vagus  nerve  has  been  cut,  that  the 
sham  feeding  no  longer  induces  a  secretion  of  gastric  juice.  The  ques- 
tion therefore  arises  as  to  how  the  nerve  center  is  stimulated.  Three 
possible  causes  may  be  considered:  (1)  mechanical  stimulation  of  the 
sensory  nerves  of  the  mouth;  (2)  chemical  stimulation  of  the  nerves; 
(3)  the  agreeable  stimulation  of  the  taste  buds  and  olfactory  endings 
concerned  in  the  tasting  of  food.  In  investigating  these  possibilities, 
mechanical  stimulation  was  readily  ruled  out  by  showing  that  mere 
taking  of  solid  matter  in  the  mouth  did  not  excite  any  secretion,  although 
it  might  cause  a  flow  of  saliva.  Mere  chemical  stimulation  could  not  be 
the  cause,  for  no  secretion  was  induced  by  placing  substances  such  as 
acetic  acid  or  mustard  oil  in  the  mouth.  By  exclusion,  then,  it  would 
appear  that  the  adequate  stimulus  must  consist  in  the  agreeable  stimula- 
tion of  the  taste  buds,  etc. — that  is  to  say,  in  the  gratification  of  appetite. 

Further  justification  for  this  conclusion  was  readily  secured  by  noting 
that  foodstuffs  for  which  the  animal  had  no  particular  desire  or  appe- 
tite failed  to  excite  the  secretion.  Most  dogs,  for  example,  although 
they  may  take  it,  are  not  particularly  fond  of  bread,  and  when  fed  with 


43  G  DIGESTION 

it,  these  animals  did  not  produce  any  appetite  juice.  In  one  animal  that 
showed  considerable  liking  for  bread,  active  secretion  occurred  when  he 
was  fed  with  this  foodstuff. 

Pavlov  further  noted  that  usually  it  was  not  necessary  actually  to 
alloAv  the  animal  to  take  the  food  into  his  mouth,  but  that  mere  teasing 
with  savory  food  was  sufficient  to  cause  the  secretion,  and  that  in 
highly  sensitive  animals  even  the  noises  and  other  events  usually  asso- 
ciated with  feeding  time  were  sufficient  to  excite  the  secretion.  In  the 
case  of  a  hungry  animal,  the  mere  approach  of  the  attendant  with  food, 
or  some  other  noise  or  action  definitely  associated  with  feeding  time, 
was  sufficient  to  excite  the  secretion.  The  appetite  juice  when  started 
was  found  to  persist  for  some  time  after  the  stimulus  causing  it  had 
been  removed. 

Carlson  has  succeeded  in  confirming  in  man  most  of  these  observa- 
tions. He  noted,  however,  that  the  secretion  produced  by  seeing  or 
smelling  or  thinking  of  food  is  much  less  than  would  be  expected  from 
Pavlov's  observations  on  dogs.  Even  when  his  subject  was  hungry, 
Carlson  did  not  observe  that  the  bringing  of  a  tray  of  savory  food  into 
the  room  caused  any  secretion  of  gastric  juice.  It  is,  of  course,  to  be 
expected  that  the  quantity  of  the  psychic  secretion  will  not  be  the  same 
in  different  individuals.  It  has  been  observed,  for  example,  by  Pavlov 
to  vary  considerably  in  the  case  of  dogs,  and  it  is  very  likely  that  it  will 
vary  still  more  in  man,  with  his  more  highly  complicated  nervous  system. 
In  no  case  could  Carlson  observe  any  secretion  of  gastric  juice  produced 
by  having  his  patient  chew  on  indifferent  substances,  or  by  stimulating 
the  nerve  endings  in  the  mouth  by  substances  other  than  those  directly 
related  to  food. 

In  man  the  rate  of  secretion  is  proportional  to  the  palat ability  of  the 
food,  the  smallest  amount,  during  twenty  minutes'  mastication  of  pal- 
atable food,  being  30  c.c.  and  the  largest  150  c.c,  in  a  series  of  156  obser- 
vations. A  typical  curve  showing  the  amount  of  the  secretion  is  given 
in  Fig.  149.  To  construct  this  curve  the  gastric  juice  was  collected  dur- 
ing five-minute  intervals  while  the  man  was  chewing  a  meal  of  average 
composition  and  of  his  oavii  choice.  An  interesting  feature  depicted  on 
this  curve  is  that  the  secretion  rate  Avas  highest  in  the  last  five-minute 
period,  this  being  the  time  during  Avhich  the  dessert  was  being  taken, 
for  which  this  man  had  a  great  relish.  Quite  clearly  there  was  a  direct 
relation  between  the  rate  of  the  secretion  of  the  appetite  juice  and  the 
palatability  of  the  food.  It  will  further  be  observed  that  it  took  only 
from  fifteen  to  twenty  minutes  after  discontinuing  the  chewing  before 
the  juice  returned  to  its  original  level. 

The  practical  application  of  these  facts  in  connection  with  the  hygiene 


PHYSIOLOGY    OF    THE    DIGKSTIVK    GLANDS 


437 


of  diet  and  the  feeding  of  patients  during  convalescence,  is  obviously 
very  great.  However  perfect  in  other  regards  a  diet  may  be,  it  will 
probably  fail  to  be  digested  at  the  proper  rate  unless  it  is  taken  with 
relish.  Frequent  feeding  with  favorite  morsels  is  more  likely  to  be  fol- 
lowed by  thorough  digestion  and  assimilation  than  occasional  stuffing 
with  larger  amounts.  We  see  too  in  these  experiments  an  explanation 
of  the  well-established  practice  of  starting  a  meal  with  something 
savory.  A  liors  d'oeuvre  is  nothing  more  than  a  physiologic  stimulant 
to  appetite.  It  is  also  interesting  from  a  practical  standpoint  to  observe 
that  with  those  who  have  a  keen  relish  for  sweetmeats  the  taking  of  des- 
sert has  a  real  physiologic  significance,  for,  as  in  Carlson's  patient,  it 
stimulates  toward  the  end  of  a  meal  a  further  secretion  of  the  gastric 


Chewing  food 

Fig.  149. — Typical  curve  of  secretion  of  gastric  juice  collected  at  5-minute  intervals  on  mas- 
tication of  palatable  food  for  20  minutes.  The  rise  in  secretion  during  the  last  5  minutes  of 
mastication  is  due  to  chewing  the  dessert  (fruit)  for  which  the  person  had  great  relish.  (From 
Carlson.) 

juice,  and  thus  insures  a  more  rapid  digestion  of  the  food.  Good  cooking, 
it  should  be  remembered,  is  really  the  first  stage  in  digestion,  and  it  is 
the  only  stage  over  which  we  can  exercise  voluntary  control. 


The  Hormone  Element  in  Gastric  Secretion 

Although  gastric  digestion  is  initiated  by  the  appetite  juice,  it  is 
clear  that  this  alone  can  not  account  for  all  the  secretion  that  occurs 
during  normal  gastric  digestion.  After  an  ordinary  meal  gastric  diges- 
tion lasts  usually  about  four  hours,  whereas  we  have  seen,  particularly 
from  Carlson's  observations,  that  the  appetite  juice  lasts  only  for  some 
fifteen  or  twenty  minutes  after  the  exciting  stimulus  has  been  removed. 
The  appetite  juice,  in  other  words,  serves  only  to  initiate  the  process  of 
secretion,  and  the  question  arises,  What  keeps  up  the  secretion  during 
the  rest  of  gastric  digestion f    The  answer  was  furnished  by  Pavlov,  who 


438  DIGESTION 

observed  animals  in  which  not  only  a  miniature  stomach  had  been  made, 
but  a  fistula  into  the  main  stomach  as  well.  The  behavior  of  the  secre- 
tion of  gastric  juice  as  a  whole  could  be  followed  by  collecting  that 
which  was  secreted  in  the  miniature  stomach,  for  it  was  shown,  in  con- 
trol experiments,  that  this  secretion  runs  strictly  parallel  with  that  in 
the  main  stomach,  being  quantitatively  a  definite  fraction  of  it — accord- 
ing to  the  relative  size  of  the  miniature  stomach — and  qualitatively 
identical.  The  miniature  stomach,  in  other  words,  mirrors  the  events 
of  secretion  in  the  main  stomach. 

It  was  observed  that  when  the  animal  was  allowed  to  take  the  food 
into  the  main  stomach  by  the  mouth  and  esophagus,  the  secretion  from 
the  miniature  stomach  continued  to  flow  until  the  process  of  gastric 
digestion  had  been  completed,  a  result  which  was  quite  different  from 
that  obtained  after  sham  feeding.  The  only  possible  explanation  for  this 
result  is  that  the  food  in  the  stomach  sets  up  secretion  as  a  result  of 
local  stimulation.  To  investigate  the  nature  of  this  local  stimulation, 
whether  mechanical  or  chemical,  food  and  other  substances  were  placed 
in  the  main  stomach  through  the  gastric  fistula  without  the  animal's 
knowledge  so  as  to  avoid  possible  psychic  stimulation,  and  the  secretion 
observed  from  the  miniature  stomach.  When  the  mucous  membrane  of 
the  main  stomach  was  stimulated  mechanically,  as  by  placing  inert 
objects  such  as  a  piece  of  sponge  or  sand  in  the  stomach,  no  secretion 
occurred.  Evidently,  therefore,  the  stimulus  is  dependent  upon  some 
chemical  quality  of  the  food. 

By  introducing  various  foods  it  was  found  that  there  is  considerable 
difference  in  the  degree  to  which  they  can  excite  the  secretion.  Water, 
egg  white,  bread  and  starch,  were  all  found  to  have  very  little  if  any 
effect.  On  the  other  hand,  when  protein  that  had  been  partly  digested 
by  means  of  pepsin  and  hydrochloric  acid  was  introduced  into  the 
stomach,  it  immediately  called  forth  a  secretion.  The  conclusion  is  that 
the  partly  digested  products,  even  of  insipid  food,  are  capable  of  directly 
exciting  the  secretion.  These  include  proteoses  and  peptones,  and  it 
was,  therefore,  of  great  interest  to  find  that  a  solution  of  commercial 
peptone  is  also  an  effective  stimulus.  This  is  a  result  of  deep  significance, 
for  it  indicates  that  the  food  which  has  been  partially  digested  by  the 
appetite  juice  will  serve  as  a  stimulus  to  continued  secretion. 

The  psychic  juice  has  been  aptly  called  the  "ignition  juice,"  because 
by  producing  partial  digestion  it  serves  to  ignite  the  process  of  gastric 
secretion.  Experimental  evidence  of  its  great  importance  in  gastric 
digestion  was  secured  by  Pavlov  in  experiments  in  which  he  placed 
weighed  quantities  of  meat  attached  to  threads  in  the  stomach  through 
a  gastric  fistula,  and  after  some  time  removed  them  and  determined  by 


PHYSIOLOGY    OF    THK    DIGESTIVE   GLANDS  439 

the  difference  in  weights  the  extent  to  which  they  had  become  digested. 
It  was  found  that  when  the  appetite  juice  was  excited  by  sham  feeding 
at  the  same  time  that  food  was  placed  directly  in  the  stomach,  its  diges- 
tion was  much  more  rapid  than  in  cases  in  which  it  was  placed  in  the 
stomach  without  the  animal's  knowing,  as  when  he  was  asleep. 

Other  foods  having  a  direct  stimulating  effect  on  the  gastric  secre- 
tion are  meat  extracts  and,  to  a  certain  extent,  milk.  This  effect  of  meat 
extract  is  interesting  in  connection  with  the  practice  of  taking  soup  as 
a  first  or  early  stage  in  dining.  It  not  only  excites  the  appetite  juice, 
but  also  serves  as  a  direct  stimulus  to  the  gastric  secretion. 

As  to  the  nature  of  the  mechanism  by  which  this  direct  secretion  takes 
place,  it  was  shown  by  Popielski10a  that  the  secretion  still  occurs  after  all 
the  nerves  proceeding  to  the  stomach  are  cut.  Evidently,  therefore,  it 
is  independent  of  the  extrinsic  nerve  supply  of  the  viscus.  As  a  result 
of  his  experiments  Popielski  concluded  that  the  secretion  must  depend 
on  a  local  reflex  mediated  through  the  nerve  structures  present  in  the 
walls  of  the  stomach  itself.  Another  explanation  of  the  result  has, 
however,  in  recent  years  been  given  more  credence  by  the  experiments  of 
Bayliss  and  Starling  on  the  influence  of  hormones  on  the  secretion  of 
pancreatic  juice  (cf.  page  425).  Edkins10  suggested  that  a  similar 
process  in  the  stomach  might  account  for  the  continued  secretion  of 
gastric  juice.  To  test  the  possibility  this  investigator,  after  ligating  the 
cardiac  sphincter  in  anesthetized  animals,  inserted  a  tube  into  the 
pyloric  end  of  the  stomach,  through  which  he  placed  in  the  stomach 
about  50  c.c.  of  physiologic  saline.  After  this  had,  been  in  the  stomach 
for  an  hour,  he  found  that  no  water  was  absorbed,  and  that  if  the  fluid 
was  removed  after  this  time,  it  contained  neither  hydrochloric  acid  nor 
pepsin.  On  the  other  hand,  if  during  the  time  the  saline  was  in  the 
stomach  a  decoction  of  the  mucous  membrane  of  the  pyloric  end,  made 
either  with  peptone  solution  or  with  a  solution  of  dextrine,  was  injected 
intravenously  in  small  quantities  every  few  minutes,  it  was  found  that 
the  saline  contained  distinct  quantities  of  hydrochloric  acid  and  pepsin. 
Furthermore,  it  was  found  that,  if  the  peptone  solution  or  the  dextrine 
solution  alone  was  injected  intravenously,  there  was  no  such  evidence 
of  gastric  secretion.  The  conclusion  which  Edkins  drew  from  his  experi- 
ments is  to  the  effect  that  the  half-digested  products  of  the  earlier  stages 
of  gastric  digestion  act  on  the  mucous  membrane  of  the  stomach  so  as  to 
produce  a  hormone,  which  is  then  carried  by  the  blood  to  the  cells  of 
the  gastric  glands,  upon  which,  like  secretin,  it  directly  develops  an 
exciting  effect.  This  hormone  has  been  called  gastrin.  These  observa- 
tions of  Edkins  have  been  confirmed,  and  they  explain  very  simply  how 
gastric  secretion  is  maintained  after  the  cessation  of  the  secretion  of  the 


440 


DIGESTION 


appetite  juice.10    By  such  a  mechanism  gastric  juice  would  continue  to  be 
secreted  so  long  as  any  half-digested  food  remains  in  the  stomach. 

The  action  of  gastrin  is  the  first  instance  of  a  hormone  control  of  the 
digestive  glands.  In  the  earlier  stages  of  digestion,  the  secretion  of  saliva 
and  appetite  juice  is  mediated  through  the  nervous  system,  because  these 
juices  must  be  produced  promptly.  In  the  later  stages  of  gastric  diges- 
tion, such  promptitude  in  response  on  the  part  of  the  gland  is  no  longer 
necessary,  so  that  the  slower,  more  continuous  process  of  hormone  con- 
trol is  sufficient. 

Quantity  of  Gastric  Juice  Secreted 

According  to  Carlson,  the  total  amount  of  gastric  juice  secreted  in 
man  on  an  average  meal  composed  of  meat,  bread,  vegetables,  coffee  or 

Hours      1234    5    678    123456789    10    123456 


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Flesh.  200  gm. 


Bread,  200  gm. 


Milk,  600  c.c. 


Fig.   150. — Cubic  centimeters  of  gastric  juice  secreted  after  diets  of  meat,   bread,  and   milk.      (From 

Pavlov.) 

milk,  and  dessert,  amounts  to  about  700  c.c,  being  divided  into  200  c.c. 
in  the  first  hour,  150  in  the  second,  and  350  c.c.  during  the  third,  fourth 
and  fifth  hours.  These  figures  were  estimated  partly  on  the  basis  of 
observations  made  on  the  man  with  the  gastric  fistula,  and  partly  from 
the  data  supplied  by  Pavlov's  observations  on  dogs.  Carlson  believes 
that  Pavlov  overestimated  the  relative-  importance  of  the  appetite  juice 
in  gastric  digestion.  He  found,  for  example,  that  after  division  of  both 
vagus  nerves  in  dogs  normal  gastric  digestion  might  be  regained  a  few 
days  after  the  operation,  although,  of  course,  under  such  circumstances  no 
appetite  juice  could  have  been  secreted.  Moreover,  he  observed  that  cats 
when  forcibly  fed  with  unpalatable  food  may  digest  that  food  as  rapidly 
as  when  they  eat  voluntarily.  In  support  of  his  contention,  Carlson 
states  that  he  has  frequently  removed  all  of  the  appetite  juice  from  his 
patient's  stomach  before  the  masticated  meal  was  put  into  it  without 
any  evident  interference  with  the  digestive  process. 

Fat  has  a  distinct  inhibiting  influence  on  the  direct  secretion  of  gas- 


PHYSIOLOGY   OF    THE   DIGESTIVE   GLANDS 


441 


trie  juice;  cream  takes  considerably  longer  to  be  be  digested  than  milk, 
and  the  presence  of  oil  in  the  stomach  delays  the  secretion  of  juice  poured 
out  on  a  subsequent  meal  of  otherwise  readily  digestible  food.  By  col- 
lecting all  of  the  gastric  juice  from  the  miniature  stomach  after  feeding 
by  mouth  with  quantities  of  different  protein-rich  foods  containing  the 
same  quantities  of  nitrogen,  interesting  observations  have  been  recorded 
concerning  the  amount  of  juice  secreted  and  its  proteolytic  power.  The 
results  of  some  of  the  experiments  are  shown  in  the  accompanying 
curves  (Figs.  150  and  151). 

It  will  be  seen  that  the  most  abundant  secretion  occurs  with  meat,  that 
of  milk  being  not  only  smaller  but  also  slower  in  starting.  The  digestive 
power  is  greatest  in  the  case  of  bread. 

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Flesh,  200  gm. 


Bread,  200  gm. 


Milk,  600  c.c. 


Fig.    151. — Digestive  power  of  the  juice,   as  measured  by  the  length   of  the   protein   column   digested 
in   Mett's   tubes,    with    diets    of   flesh,    bread,    and    milk.      (From    Pavlov.) 


THE  INTESTINAL  SECRETIONS 


Pancreatic  Juice 

Kegarding  the  natural  secretion  of  pancreatic  juice,  little  need  be  added 
to  what  has  already  been  said  (see  page  425) .  The  secretion  begins  when  the 
chyme  enters  the  duodenum,  and  attains  its  maximum  when  the  outflow 
of  this  is  greatest.  By  collecting  the  juice  from  a  permanent  fistula  of  the 
pancreatic  duct,  it  has  been  found  that  the  amount  varies  with  different 
foods.  When  quantities  of  food  containing  equivalent  amounts  of  nitro- 
gen are  fed,  the  greatest  secretion  is  said  to  occur  with  bread  and  the  least 
with  milk.  Such  differences  are  probably  dependent  upon  the  amount  of 
acid  secreted  in  the  stomach  and  passed  on  into  the  duodenum.  It  was 
thought  at  one  time  that,  besides  variation  in  quantity,  the  nature  of  the 
enzymes  in  the  pancreatic  juice  might  vary  according  to  the  kind  of 
food.    This,  however,  has  been  shown  not  to  be  the  case. 


442 


DIGESTION 


Bile 

The  secretion  of  bile  runs  practically  parallel  with  that  of  pancreatic 
juice.  The  liver  is  producing  bile  more  or  less  continuously,  since  besides 
being  a  digestive  fluid  it  is  also  an  excretory  product,  The  bile  produced 
between  the  periods  of  digestion  is  mainly  stored  in  the  gall  bladder. 
When  the  acid  chyme  comes  in  contact  with  the  duodenal  mucous  mem- 
brane, it  excites  afferent  nerve  endings  that  cause  a  reflex  contraction  of 
the  gall  bladder,  and  this  expresses  some  of  the  bile  into  the  duodenum. 
The  secretin,  which  the  acid  at  the  same  time  produces,  besides  affecting 
the  pancreas,  acts  on  the  liver  cells,  stimulating  them  to  the  increased 
secretion  of  bile.  Thus,  by  a  nervous  reflex  operating  on  the  gall  bladder 
and  later  by  a  hormone  mechanism  operating  on  the  liver  cell,  the  increased 
secretion  of  bile  is  insured  throughout  digestion.  Of  the  bile  discharged 
into  the  intestine,  a  certain  proportion  of  the  bile  salts  is  reabsorbed  into 
the  portal  blood.  When  these  arrive  at  the  liver  they  also  excite  secre- 
tion of  bile,  thus  assisting  secretin  in  maintaining  the  secretion  through- 
out the  process  of  intestinal  digestion. 


Fig.    152. — Loop   of  intestine  after   tying  off  the   portions,   cutting  the   nerves   running   to   the   middle 
portion,    and   returning   the    loop    to    the   abdomen    for   some    time.      (From   Jackson.) 


Intestinal  Juice 

The  secretion  of  intestinal  juice,  or  succus  entericus,  can  obviously  be 
studied  only  after  isolating  portions  of  the  intestine  and  connecting  them 
with  fistulas  of  the  abdominal  walls.  It  appears  here  again  that  both  a 
nervous  and  a  hormone  mechanism  exist.  Mechanical  stimulation  of  the 
intestinal  mucous  membrane  causes  an  immediate  outflow  of  intestinal 
juice,  the  purpose  of  which  under  normal  conditions  is  evidently  to  assist 
in  moving  forward  the  bowel  contents.  This  mechanically  excited  juice 
does  not  contain  any  enterokinase  and  only  small  amounts  of  the  other 
enzymes.  Further  evidence  for  nervous  control  of  the  secretion  of  intes- 
tinal juice  has  been  obtained  by  isolating  three  pouches  of  intestine  be- 


PHYSIOLOGY   OF   THE   DIGESTIVE   GLANDS  443 

tween  ligatures,  and  then  denervating  the  central  punch  by  carefully 
cutting-  all  the  nerves  without  wounding  the  blood  vessels.  On  returning 
the  pouches  to  the  abdomen  and  Leaving  them  Beveral  hours,  it  has  been 
found  that  the  middle  pouch  becomes  distended  with  secretion,  whereas 
the  two  end  pouches  remain  empty  (Fig.  152).  If  the  pouches  are  left  for 
several  days  in  the  abdomen,  however,  the  secretion  from  the  denervated 
portion  disappears  again.  The  explanation  of  the  result  is  possibly  that 
the  nerves  under  ordinary  conditions  convey  impulses  to  the  intestinal 
glands,  which  tonically  inhibit  their  activity. 

The  existence  of  hormone  control  is  evidenced  by  the  fact  that  no 
enterokinase  is  present  in  the  intestinal  juice  unless  pancreatic  juice  is 
placed  in  contact  with  the  mucous  membrane.  Injection  of  pancreatic 
juice  into  the  blood,  however,  does  not  cause  any  secretion  of  intestinal 
juice ;  whereas  the  injection  of  secretin  has  such  an  effect. 


CHAPTER  LI 

THE  MECHANISMS  OF  DIGESTION 

MASTICATION,  DEGLUTITION,  VOMITING 

Mastication 

By  the  movements  of  the  lower  jaw  on  the  upper,  the  two  rows  of 
teeth  come  together  so  as  to  serve  for  biting  or  crushing  the  food.  The 
resulting  comminution  of  the  food  forms  the  first  step  in  digestion.  The 
up  and  down  motion  of  the  lower  jaw  results  in  biting  by  the  incisors, 
and  after  the  mouthful  has  been  taken,  the  side  to  side  movements  enable 
the  grinding  teeth  to  crush  and  break  it  up  into  fragments  of  the  proper 
size  for  swallowing.  The  most  suitable  size  of  the  mouthful  is  about 
5  c.c,  but  this  varies  greatly  with  habit.  After  mastication,  the  mass 
weighs  from  3.2  to  6.5  gm.,  about  one-fourth  of  this  weight  being  due  to 
saliva.  The  food  is  now  a  semifluid  mush  containing  particles  which 
are  usually  less  than  2  mm.  in  diameter.  Some,  however,  may  measure 
7  or  even  12  mm. 

Determination  of  the  proper  degree  of  fineness  of  the  food  is  a  func- 
tion of  the  tongue,  gums,  and  cheeks,  for  which  purpose  the  mucous 
membrane  covering  them  is  supplied  with  very  sensitive  touch  nerve 
endings  (see  page  794).  The  sensitiveness  of  the  tongue,  etc.,  in  this 
regard  explains  why  an  object  which  can  scarcely  be  felt  by  the  fingers 
seems  to  be  quite  large  in  the  mouth.  If  some  particles  of  food  that  are 
too  large  for  swallowing  happen  to  be  carried  backward  in  the  mouth, 
the  tongue  returns  them  for  further  mastication. 

The  saliva  assists  in  mastication  in  several  ways:  (1)  by  dissolving 
some  of  the  food  constituents;  (2)  by  partly  digesting  some  of  the 
starch;  (3)  by  softening  the  mass  of  food  so  that  it  is  more  readily 
crushed;  (4)  by  covering  the  bolus  with  mucus  so  as  to  make  it  more 
readily  transferable  from  place  to  place.  The  secretion  of  saliva  is 
therefore  stimulated  by  the  chewing  movements,  and  its  composition 
varies  according  to  the  nature  of  the  food  (page  431).  In  some  animals, 
such  as  the  cat  and  dog,  mastication  is  unimportant,  coating  of  the  food  with 
saliva  being  the  only  change  which  it  undergoes  in  the  mouth.  In  man 
the  ability  thus  to  bolt  the  food  can  readily  be  acquired,  not,  however, 
without  some  detriment  to  the  efficiency  of  digestion  as  a  whole.     Soft 

444 


THE    MECHANISMS   OF    DIGESTION  445 

starchy  food  is  little  chewed,  the  length  of  time  required  for  the  mastica- 
tion of  other  foods  depending  mainly  on  their  nature,  but  also  to  a 
certain  degree  on  the  appetite  and  on  the  size  of  the  mouthful. 

It  can  not  be  too  strongly  insisted  upon  that  the  act  of  mastication  is 
of  far  more  importance  than  merely  to  break  up  and  prepare  the  food 
for  swallowing.  It  causes  the  food  to  be  moved  about  in  the  mouth  so  as 
to  develop  its  full  effect  on  the  taste  buds;  the  crushing  also  releases 
odors  which  stimulate  the  olfactory  epithelium.  On  these  stimuli  depend 
the  satisfaction  and  pleasure  of  eating,  which  in  turn  initiate  the  process 
of  gastric  digestion  (see  page  435). 

The  benefit  to  digestion  as  a  whole  of  a  large  secretion  of  saliva,  brought 
about  by  persistent  chewing,  has  been  assumed  by  some  to  be  much 
greater  than  it  really  is,  and  there  has  existed,  and  indeed  may  still 
exist,  a  school  of  faddists  who,  by  deliberately  chewing  far  beyond 
the  necessary  time,  imagine  themselves  to  thrive  better  on  less  food  than 
those  who  occupy  their  time  with  more  profitable  pursuits. 

Deglutition  or  Swallowing 

After  being  masticated  the  food  is  rolled  up  into  a  bolus  by  the  action 
of  the  tongue  against  the  palate,  and  after  being  lubricated  by  saliva  is 
moved,  by  elevation  of  the  front  of  the  tongue,  towards  the  back  of  the 
mouth.  This  constitutes  the  first  stage  of  swallowing,  and  is,  so  far,  a 
voluntary  act.  About  this  time  a  slight  inspiratory  contraction  of  the 
diaphragm  occurs — the  so-called  respiration)  of  swallowing — and  the 
mylohyoid  quickly  contracts,  with  the  consequence  that  the  bolus  passes 
between  the  pillars  of  the  fauces.  This  marks  the  beginning  of  the 
second  stage,  the  first  event  of  which  is  that  the  bolus,  by  stimulating 
sensory  nerve  endings,  acts  on  nerve  centers  situated  in  the  medulla 
oblongata  so  as  to  cause  a  coordinated  series  of  movements  of  the 
muscles  of  the  pharynx  and  larynx  and  an  inhibition  for  a  moment  of 
the  respiratory  center    (page  332). 

The  movements  alter  the  shape  of  the  pharynx  and  of  the  various 
openings  into  it  in  such  a  manner  as  to  compel  the  bolus  of  food  to  pass 
into  the  esophagus  (see  Fig.  153):  thus,  (1)  the  soft  palate  becomes 
elevated  and  the  posterior  wall  of  the  pharynx  bulges  forward  so  as  to 
shut  off  the  posterior  nares,  (2)  the  posterior  pillars  of  the  fauces  ap- 
proximate so  as  to  shut  off  the  mouth  cavity,  and,  (3)  in  about  a  tenth  of 
a  second  after  the  mylohyoid  has  contracted,  the  larynx  is  pulled  up- 
wards and  forwards  under  the  root  of  the  tongue,  which  by  being 
drawn  backwards  becomes  banked  up  over  the  laryngeal  opening.  This 
pulling  up  of  the  larynx  brings  the  opening  into  it  near  to  the  lower 
half  of  the  dorsal  side  of  the  epiglottis,  but  the  upper  half  of  this  struc- 


446 


DIGESTION 


ture  projects  beyond  and  serves  as  a  ledge  to  guide  the  bolus  safely  past 
this  critical  part  of  its  course.  (4)  As  a  further  safeguard  against  any 
entry  of  food  into  the  air  passages,  the  laryngeal  opening  is  narrowed  by 
approximation  of  the  true  and  the  false  vocal  cords. 

So  far  the  force  which  propels  the  bolus  is  mainly  the  contraction  of 
the  mylohyoid,  assisted  by  the  movements  of  the  root  of  the  tongue. 
When  it  has  reached  the  lower  end  of  the  pharynx,  however,  the  bolus 
readily  falls  into  the  esophagus,  which  has  become  dilated  on  account 
of  a  reflex  inhibition  of  the  constrictor  muscles  of  its  upper  end.  This  so- 
called  second  stage  of  swallowing  is,  therefore,  a  complex  coordinated 
movement  initiated  by  afferent  stimuli  and  involving  reciprocal  action 
of  various  groups  of  muscles:  inhibition  of  the  respiratory  muscles  and 


Fig.  153. — The  changes  which  take  place  in  the  position  of  the  root  of  the  tongue,  the  soft 
palate,  the  epiglottis  and  the  larynx  during  the  second  stage  of  swallowing.  The  thick  dotted  line 
indicates   the   position   during   swallowing. 

of  those  that  constrict  the  esophagus,  and  stimulation  of  those  that 
elevate  the  palate,  the  root  of  the  tongue,  and  the  larynx.  It  is  purely 
an  involuntary  process. 

The  third  stage  of  deglutition  consists  in  the  passage  of  the  swallowed 
food  along  the  esophagus.  The  mechanism  by  which  this  is  done  de- 
pends very  much  on  the  physical  consistence  of  the  food.  A  solid  bolus 
that  more  or  less  fills  the  esophagus  excites  a  typical  peristaltic  wave, 
which  is  characterized  by  a  dilatation  of  the  esophagus  immediately  in 
front  of  and  a  constriction  over  and  behind  the  bolus.  This  wave  travels 
down  the  esophagus  in  man  at  such  a  rate  that  it  reaches  the  cardiac 
sphincter  in  about  five  or  six  seconds.     On  arriving  here  the  cardiac 


Till'.    Ml  (NANISMS    OF    DIGESTION  447 

sphincter,  ordinarily  contracted,  relaxes  for  a  moment  so  that  the  bolus 
passes  into  the  stomach.  In  many  animals,  including  man  and  the  cat, 
the  peristaltic  wave  1  ravels  much  more  rapidly  in  the  upper  part  of  the 
esophagus  than  lower  down  because  of  differences  in  the  nature  of  the 
muscular  coat,  this  being  of  the  striated  variety  above,  and  of  the  non- 
striated  below.  The  purpose  of  more  rapid  movement  in  the  upper  part 
is  no  doubt  that  the  bolus  may  be  hurried  past  the  regions  where,  by 
distending  the  esophagus,  it  might  interfere  with  the  function  of  neigh- 
boring structures,  such  as  the  heart.  In  other  animals,  as  the  dog,  the 
muscular  fiber  is  striated  all  along  the  esophagus,  and  the  bolus  of  food 
correspondingly  travels  at  a  uniform,  quick  rate  all  the  way.  It  takes 
only  about  four  seconds  for  the  bolus  to  reach  the  stomach  in  the  dog. 

The  peristaltic  wave  of  the  upper  part  of  the  esophagus  in  the  cat  and 
presumably  in  man,  unlike  that  of  the  intestines  (see  page  466),  is  trans- 
mitted by  the  esophageal  branches  of  the  vagus  nerves.  If  these  are 
severed,  but  the  muscular  coats  left  intact,  the  esophagus  becomes  dilated 
above  the  level  of  the  section  and  contracted  below,  and  no  peristaltic 
wave  can  pass  along  it;  on  the  other  hand,  the  muscular  coat  may  be 
severed  (by  crushing,  etc.)  but  the  peristaltic  wave  will  continue  to 
travel,  provided  no  damage  has  been  done  to  the  nerves. 

In  the  lower  part  of  the  esophagus,  however,  the  wave  of  peristalsis, 
like  that  of  the  intestines,  travels  independently  of  extrinsic  nerves. 
This  has  been  observed  in  animals  in  which  all  of  the  extrinsic  nerves 
have  been  cut  some  time  previously.  This  difference  between  the  upper 
and  the  lower  portions  is  associated  with  the  difference  in  the  nature  of 
the  muscular  fibers  above  noted  (Meltzer).11  ' 

The  propagation  of  the  wave  by  the  nerves  in,  the  upper  part  of  the 
esophagus  indicates  that  the  second  stage  and  the  first  part  of  the  third 
stage  of  deglutition  must  be  rehearsed,  as  it  were,  in  the  medullary 
centers  from  which  arise  the  nerve  fibers  to  the  pharynx  and  the  upper 
levels  of  the  esophagus.  It  is  thought  that  the  discharges  from  these 
local  centers  are  controlled  by  a  higher  swallowing  center  situated  in  the 
medulla  just  above  that  of  respiration,  the  afferent  stimuli  to  which 
proceed  from  the  pharynx  by  the  fifth,  superior  laryngeal,  and  vagus 
nerves.  The  exact  location  of  the  sensory  areas  whose  stimulation  is 
most  effective  in  initiating  the  swallowing  reflex  varies  considerably 
in  different  animals.  In  man  it  is  probably  at  the  entrance  to  the 
pharynx;  in  the  dog  it  is  on  the  posterior  wall.  A  foreign  body  placed 
directly  in  the  upper  portion  of  the  esophagus  of  man  has  been  observed 
to  remain  stationary  until  the  individual  made  a  swallowing  movement. 
The  afferent  fibers  in  the  glossopharyngeal  nerve  exercise  a  powerful 
inhibitory  influence  on  the  deglutition  center  as  well  as  on  that  of  respira- 


448  DIGESTION 

tion.  Thus,  if  swallowing  movements  are  excited  by  stimulating  the  cen- 
tral end  of  the  superior  laryngeal  nerve,  they  can  be  instantly  inhibited 
by  simultaneously  stimulating  the  glossopharyngeal,  and  the  respiratory 
movements  stop  in  whatever  position  they  may  have  been  at  the  time. 
When  the  glossopharyngeal  nerves  are  cut,  the  esophagus  enters  into  a 
condition  of  tonic  contraction,  which  may  last  a  day  or  so.  This  shows 
that  the  inhibitory  impulses  are  tonic  in  nature. 

This  inhibition  of  the  esophagus  is  indeed  a  most  important  part  of 
the  process  when  liquid  or  semiliquid  food  is  swallowed.  By  the  contrac- 
tion of  the  mylohyoid  muscle,  fluids  are  quickly  shot  down  the  distended 
esophagus,  at  the  lower  end  of  which,  on  account  of  the  closure  of  the 
cardiac  sphincter,  they  accumulate  until  the  arrival  of  the  peristaltic 
wave  which  has  meanwhile  been  set  up  by  stimulation  of  the  pharynx. 
If  the  swallowing  is  immediately  repeated,  as  is  usually  the  case  in 
drinking,  the  esophagus  remains  dilated  because  peristalsis  is  inhibited, 
and  the  fluid  lies  outside  the  cardiac  orifice  until  the  last  mouthful  has 
been  taken. 

The  Cardiac  Sphincter 

The  passage  between  the  esophagus  and  the  stomach  is  guarded  by 
the  cardiac  sphincter  or  cardia.  This  exists  in  a  permanently  con- 
tracted state,  or  tonus,  superimposed  on  which  from  time  to  time  are 
rhythmic  alternations  of  contraction  and  relaxation.  This  tonus  is  never 
very  pronounced.  In  man  it  is  said  that  a  water  pressure  of  from  2  to  7 
cm.  applied  to  the  esophageal  side  of  the  sphincter  will  drive  air  or 
water  into  the  stomach,  this  pressure  being  less  than  that  of  a  column 
of  fluid  filling  the  thoracic  esophagus  in  the  erect  position.  During 
repeated  deglutition  the  tonus  becomes  less  and  less  marked,  and  after 
a  number  of  swallows  the  sphincter  may  become  completely  relaxed. 
When  this  relaxation  disappears,  however,  the  sphincter  becomes  more 
contracted  than  usual  and  remains  so  for  a  longer  time. 

The  tonic  condition  of  the  sphincter  is  controlled  by  the  vagus  nerve, 
stimulation  of  which  causes  relaxation  with  an  after-effect  of  strong 
contraction.  Mechanical  or  chemical  stimulation  of  the  lower  end  of  the 
esophagus  increases  the  tonus  of  the  sphincter.  Forcing  of  the  sphincter 
from  the  stomach  side  requires  a  higher  pressure  than  from  the  esopha- 
geal. Eructation  of  gas,  for  example,  does  not  take  place  until  intra- 
gastric pressure  has  risen  to  about  25  cm.  of  water.  In  deep  anesthesia, 
however,  intragastric  pressure  may  rise  considerably  higher  without 
forcing  the  sphincter. 

In  animals  fed  with  starch  paste  impregnated  with  subnitrate  of  bis- 
muth and  then  examined  by  means  of  the  x-rays,  the  variation  in  degree 


THE    MECHANISMS   OF    DIGESTION  449 

of  tone  of  the  sphincter  has  been  observed  t<>  be  responsible  for  occasional 
regurgitation  of  some  of  the  gastric  contents  into  the  esophagus  up  to  the 
level  of  the  heart  or  even  to  the  base  of  the  neck.  The  presence  of  the 
gastric  contents  in  the  esophagus  starts  a  peristaltic  wave,  which  pushes 
the  material  back  again  into  the  stomach.  This  peristaltic  wave  starts 
in  the  absence  of  any  other  phases  of  the  deglutition  process,  indicating 
that  it  has  been  excited  by  the  presence  of  the  material  in  the  esophagus 
itself,  and  belongs,  therefore,  to  the  lower  order  of  peristaltic  wave,  as 
seen  in  the  intestines  but  not  in  the  upper  half  of  the  esophagus.  Regur- 
gitation of  food  into  the  esophagus  occurs  only  when  the  intragastric 
pressure  is  fairly  high.  Tt  may  last  for  a  period  of  from  twenty  to  thirty 
minutes  after  the  meal  is  taken,  and  disappears  when  the  tonus  of  the 
sphincter  becomes  increased  as  a  result  of  the  presence  in  the  gastric 
contents  of  free  hydrochloric  acid. 

Much  information  has  been  secured  by  listening  with  a  stethoscope  to 
tlie  sounds  caused  In;  swallowing  and  by  observing  with  the  x-ray  the 
shadows  produced  along  the  course  of  the  esophagus  when  food  impreg- 
nated with  bismuth  subnitrate  is  taken.  When  a  solid  bolus  is  swal- 
lowed only  one  sound  is  usually  heard,  but  with  liquid  food  there  are 
two,  one  at  the  upper  end,  due  to  the  rush  of  the  fluid  and  air,  and 
the  other  at  the  lower  end  (heard  over  the  epigastrium),  four  or  six 
seconds  later,  due  to  the  arrival  here  of  the  peristaltic  wave  with  the 
accompanying  opening  of  the  cardiac  sphincter  and  the  escape  of  the 
fluid  and  air  into  the  stomach.  Sometimes,  when  the  person  is  in  the 
horizontal  position,  this  second  sound  may  be  broken  up  into  several, 
indicating  that,  unassisted  by  gravity,  the  fluid  does  not  so  readily  pass 
through  the  sphincter.  The  x-ray  shadows  yield  results  in  conformity 
with  the  above.  After  SAvallowing  milk  and  bismuth,  for  example,  the 
shadow  falls  quickly  to  the  lower  end  of  the  esophagus  and  then  passes 
slowly  into  the  stomach.  When  the  passage  of  a  solid  bolus  is  watched 
by  the  x-ray  method,  its  rate  of  descent  will  be  found  to  depend  on 
whether  or  not  it  is  well  lubricated  with  saliva;  if  not  so,  it  may  take  as 
long  as  fifteen  minutes  to  reach  the  stomach;  if  moist,  but  from  eight 
to  eighteen  seconds. 

Vomiting 

Vomiting  is  usually  preceded  by  a  feeling  of  sickness  or  nausea,  and 
is  initiated  by  a  very  active  secretion  of  saliva.  The  saliva,  mixed  with 
air,  accumulates  to  a  considerable  extent  at  the  lower  end  of  the  esopha- 
gus, which  it  distends.  A  forced  inspiration  is  now  made,  during  the 
first  stage  of  which  the  glottis  is  open  so  that  the  air  enters  the  lungs, 
but  later  the  glottis  closes  so  that  the  inspired  air  is  sucked  into  the 


450  DIGESTION 

esophagus,  which,  already  somewhat  distended  by  saliva,  now  becomes 
markedly  so.  The  abdominal  muscles  then  contract  so  as  to  compress 
the  stomach  against  the  diaphragm  and,  simultaneously,  the  cardiac 
sphincter  relaxes,  the  head  is  held  forward  and  the  contents  of  the 
stomach  are  ejected  through  the  previously  distended  esophagus.  The 
compression  of  the  stomach  by  the  contracting  abdominal  muscles  is 
assisted  by  an  actual  contraction  of  the  stomach  itself,  as  has  been  clearly 
demonstrated  by  the  x-ray  method.  After  the  contents  of  the  stomach 
itself  have  been  evacuated,  the  pyloric  sphincter  may  also  relax  and 
permit  the  contents  (bile,  etc.)  of  the  duodenum  to  be  vomited. 

The  act  of  vomiting  is  controlled  by  a  center  located  in  the  medulla, 
and  the  afferent  fibers  to  this  center  may  come  from  many  different 
regions  of  the  body.  Perhaps  the  most  potent  of  them  come  from  the 
sensory  nerve  endings  of  the  fauces  and  pharynx.  This  explains  the 
tendency  to  vomit  when  the  mucosa  of  this  region  is  mechanically  stimu- 
lated. Other  afferent  impulses  come  from  the  mucosa  of  the  stomach 
itself,  and  these  are  stimulated  by  emetics,  important  among  which  are 
strong  salt  solution,  mustard  water  and  zinc  sulphate.  Certain  other 
emetics,  particularly  tartar  emetic  and  apomorphine,  act  on  the  vomit- 
ing center  itself,  and  can  therefore  operate  when  given  subcutaneously. 
Afferent  vomiting  impulses  also  arise  from  the  abdominal  viscera,  thus 
explaining  the  vomiting  which  occurs  in  strangulated  hernia,  and  in 
other  irritative  lesions  involving  this  region.  X-ray  observations  have 
been  made  on  the  movements  of  the  stomach  of  cats  after  the  admin- 
istration of  apomorphine  (Cannon).  The  first  change  observed  is  an 
inhibition  of  the  cardiac  end  of  the  stomach,  which  becomes  a  perfectly 
flaccid  bag.  About  the  midregion  of  the  organ,  deeper  contractions  then 
start  up,  which  sweep  from  the  pylorus,  each  contraction  stopping  as  a 
deep  ring  at  the  beginning  of  the  vestibule,  Avhile  a  slighter  wave  con- 
tinues. A  very  strong  contraction  at  the  incisura  angularis  finally 
develops  and  completely  divides  the  gastric  cavity  into  two  parts.  On 
the  left  of  this  constriction  the  stomach  remains  completely  relaxed,  but 
at  the  right  of  it  waves  continue  running  over  the  vestibule.  It  is  while 
the  stomach  is  in  this  condition  that  the  sudden  contraction  of  the  dia- 
phragm and  abdominal  muscles  shoots  the  cardiac  contents  into  the 
relaxed  esophagus.  As  these  jerky  contractions  are  continued,  the  gastric 
walls  seem  to  reacquire  their  tone. 


CHAPTER  LII 
THE  MECHANISMS  OF  DIGESTION   (Cont'd) 

THE  MOVEMENTS  OF  THE  STOMACH 

The  Character  of  the  Movements 

Even  from  the  earliest  days  it  has  been  recognized  that  the  stomach 
performs  two  important  f mictions:  (1)  receiving  the  SAvallowed  food 
and  then  discharging  it  slowly  into  the  intestine,  and  (2)  initiating  the 
chemical  processes  of  digestion.  In  order  to  understand  the  mechanism 
by  which  the  stomach  collects  and  then  discharges  the  food,  it  is  neces- 
sary first  of  all  to  recall  certain  anatomic  facts  concerning  the  organ, 
and  for  this  purpose  it  is  most  convenient  to  accept  the  description 
given  by  Cannon,  which  is  illustrated  in  the  accompanying  figure.  The 
organ  is  divided  into  a  cardiac  and  a  pyloric  portion  by  a  deep  notch  in 
the  lesser  curvature,  called  the  incisura  angularis.  The  cardiac  portion 
is  further  subdivided  into  two  by  the  cardiac  orifice.  The  part  which 
lies,  in  man,  above  a  line  drawn  horizontally  through  the  cardia  is  the 
fundus.  The  part  lying  between  the  fundus  and  the  incisura  angularis 
is  known  as  the  body  of  the  stomach,  which,  when  full,  has  a  tapering 
shape.  The  pyloric  portion  lying  on  the  right  of  the  incisura  angularis 
is  further  divided  into  two  parts:  the  pyloric  vestibule  and  the  pyloric 
canal,  the  latter  of  which  lies  next  the  pyloric  sphincter  and  in  man 
measures  about  3  cm.  in  length  (see  Fig.  154). 

The  filled  stomach  of  a  person  standing  erect  is  so  disposed  that  the 
greatest  curvature  forms  its  lowest  point,  which  may  be  considerably 
below  the  umbilicus.  As  digestion  proceeds  and  the  stomach  empties, 
the  greater  curvature  becomes  gradually  raised,  so  that  ultimately  the 
pylorus  comes  to  be  the  most  dependent  part  of  the  stomach.  From 
these  and  many  other  observations  it  is  certain  that  the  emptying  of  the 
stomach  does  not  at  all  depend  on  the  operation  of  the  force  of  gravity. 
Indeed,  that  this  can  not  be  the  case  is  perfectly  clear  when  we  con- 
sider the  disposition  of  the  stomach  in  quadrupeds. 

Exact  observation  on  the  movements  which  the  stomach  performs  from 
the  time  it  is  filled  with  food  till  it  empties,  have  been  made  by  the 
x-ray  method,  first  introduced  by  Cannon.12    The  method  consists  in  feed- 

451 


452 


DIGESTION 


ing  the  animal  with  food  that  has  been  impregnated  with  bismuth  sub- 
nitrate,  then  exposing  him  to  the  x-ray  and  either  taking  instantaneous 
photographs  of  the  shadows  or  observing  them  by  means  of  a  fluorescent 
screen.     The  descriptions  of  the  original  observations  made  by  Cannon 


Fig.    154. — Schematic    outline    of    the    stomach.      At    C    is    the    cardia;    F,    fundus;    I  A,    incisura    an- 
nularis;   D,   body;   PC,  pyloric   canal;   P,  pylorus.      (From   Cannon.) 

on  the  stomach  of  the  cat  have  been  so  little  modified  by  observations 
on  man  that  Ave  may  take  them  as  a  convenient  type.  In  the  accompany- 
ing figure  (Fig.  156)  the  outline  of  the  shadow  cast  by  the  stomach  is 
shown  at  intervals  of  an  hour  each  during  digestion.     Soon  after  the 


Fig.  155. — Diagrams  of  outline  and  position  of  stomach  as  indicated  by  skiagrams  taken  on 
man  in  the  erect  position  at  intervals  after  swallowing  food  impregnated  with  bismuth  subnitrate. 
A,  moderately  full;  B.  practically  empty.  The  clear  si. ace  at  the  upper  end  of  the  stomach  is  due 
to  gas,  and  it  will  be  noticed  that  this  "stomach  bladder"  lies  close  to  the  heart.  (From  T.  Win- 
gate   Todd.) 


THE    MECHANISMS   ()K    DIGESTION 


453 


stomach  has  become  filled,  peristaltic  waves  are  seen  to  take  their 
origin  about  the  middle  of  the  body  of  the  stomach,  and  to  course 
towards  the  pylorus.  Above  the  region  a1  which  these  waves  originate — 
that  is,  the  eardiac  half  of  the  body  of  the  stomach  and  all  of  the 
fundus-  there  are  no  waves,  but  as  digestion  proceeds  the  walls  slowly 
and  steadily  contract  on  the  mass  of  food.  This  so-called  cardiac  pouch 
does  not,  however,  diminish  in  size  so  rapidly  as  the  part  of  the  body  of 
the  stomach  over  which  the  peristaltic  waves  are  passing.  The  circular 
fibers  of  the  walls  of  this  part  of  the  stomach — sometimes  called  the 
gastric  tube — contract  tonically,  so  that  it  becomes  tubular  in  form, 
with  the  full  cardiac  pouch  at  the  left  and  above  and  the  pyloric  por- 


Kig.   156. — Outlines     of  the  shadows  cast  by  the  stomach  at  intervals  of  an   hour  each   after  feeding 
a    cat    with    food    impregnated    with    bismuth    subnitrate.       (From    Cannon.) 

tion  at  the  right.  The  latter  portion  meanwhile  does  not  diminish  much 
in  size,  although  the  peristaltic  waves  traveling  over  it  are  very  pro- 
nounced. As  will  be  clear  from  the  figure,  these  changes  in  outline  go 
on  until  the  cardiac  pouch  has  become  practically  empty  and  the  food 
has  been  all  moved  along  the  now  tubular  portion  of  the  body  into  the 
pyloric  vestibule. 

From  this  description  it  is  evident  that  the  function  of  the  cardiac 
end  is  to  serve  as  a  reservoir  for  the  food,  which,  by  a  slow  contraction 
of  the  walls,  is  gradually  delivered  into  the  gastric  tube,  where  by 
peristalsis  it  is  carried  towards  the  pyloric  vestibule. 

The  time  required  for  the  peristaltic  waves  to  travel  from  their  place 
of  origin  to  the  pylorus  is  considerably  longer  than  the  interval  between 


454  DIGESTION 

the  waves,  so  that  several  of  these  are  always  seen  on  the  stomach  at 
the  same  time.  They  sometimes  become  so  pronounced  in  the  pyloric 
region,  especially  in  a  half-empty  stomach,  that  they  appear  almost  to 
obliterate  the  cavity.  They  always  stop  at  the  pylorus,  never  going  on 
to  the  duodenum.  The  rate  of  recurrence  of  the  waves  varies  somewhat 
in  different  animals,  being  about  six  per  minute  in  the  oat  and  about 
three  in  man.  Their  initiation  does  not  seem  to  depend  on  the  presence 
of  acid  in  the  gastric  contents,  for,  when  food  Is  introduced  into  the 
stomach,  they  do  not  wait  for  the  gastric  contents  to  become  acid  in 
reaction  (see  page  482).  Nevertheless,  acid  does  seem  somewhat  to  stim: 
ulate  the  depth  and  frequency  of  the  waves,  and  they  recur  oftener  with 
carbohydrate  than  with  fatty  food. 

The  pressure  in  the  stomach  contents — the  intragastric  pressure — is 
low  and  constant  at  the  cardiac  end  and  fairly  high  and  variable  in  the 
pyloric  end  (in  the  former  from  6  to  8  cm.  of  water,  and  in  the  latter 
from  20  to  30).  Constancy  of  pressure  in  the  cardiac  end  indicates 
that  the  stomach  wall  must  adapt  itself  very  promptly  to  the  amount  of 
food  in  the  organ.  The  higher  and  more  variable  pressure  in  the  pyloric 
end  is,  of  course,  due  to  the  peristaltic  waves,  and  it  is  interesting  to  note 
that  it  is  sufficient  to  propel  the  gastric  contents  through  the  pylorus  for 
several  centimeters  into  the  duodenum. 

The  Effect  of  the  Stomach  Movements  on  the  Food 

This  has  been  studied:  (1)  by  dividing  the  food  into  portions  that 
are  differently  colored  and,  after  some  time,  killing  the  animal,  freezing 
the  stomach  and  making  sections  of  it  (see  Fig.  157)  ;  (2)  by  mak- 
ing little  pellets  of  bismuth  subnitrate  with  starch  and  observing  their 
behavior  under  the  x-rays;  or  (3)  by  removing  samples  of  the  stomach 
contents  by  means  of  a  stomach  tube  (Rehfuss  tube)  inserted  so  that 
its  free  end  lies  in  either  the  cardiac  or  the  pyloric  region.  By  the 
first  of  the  above  methods  it  has  been  found  that  the  first  mouthfuls 
of  food  lie  along  the  greater  curvature,  where  they  form  a  layer  over 
which  that  subsequently  swallowed  accumulates,  with  the  last  por- 
tions next  the  cardia.  The  pepsin  and  hydrochloric  acid  of  the  car- 
diac end,  therefore,  act  soonest  on  the  first  swallowed  portion  of  a 
meal,  and  the  more  recently  swallowed  central  masses  are  not  affected 
by  the  secretions  for  some  time,  so  that  opportunity  is  given  for  the 
saliva  mixed  with  the  food  to  develop  its  digestive  action. 

As  has  been  shown  by  removing  the  stomach  contents  with  a  tube  at 
various  periods  after  feeding  with  starchy  food,  considerable  amylolysis 
may  occur  for  some  time.  When  separate  samples  are  removed  in  this 
way  from  the  cardiac  and  pyloric  parts,  it  has  been  found  that  after 


THK    MECHANISMS    OF    DIGESTION  455 

half  an  hour  the  contents  of  both  have  about  the  same  percentage  of 
sugar,  but  that  for  some  time  after  this  interval  the  cardiac  contents 
contain  considerably  more  sugar  than  the  pyloric.  Later  the  percentages 
of  sugar  again  become  about  equal,  no  doubt  on  account  of  diffusion. 
The  diastatic  action  in  the  fundus  is  finally  brought  to  an  end  when 
the  contents  become  completely  permeated  by  the  hydrochloric  acid. 
In  this  connection  it  is  worthy  of  note  that  the  addition  of  hydrochloric 
acid  up  to  the  point  of  neutrality  greatly  accelerates  the  rate  of  diastatic 
digestion. 

As  the  outer  layers  of  food  in  the  stomach  become  partly  digested  on 
account  of  the  action  of  the  pepsin  and  hydrochloric  acid,  the  food  is 
slowly  pressed  into  the  active  right  half  of  the  stomach,  where  by  the 
action  of  the  peristaltic  waves  it  is  moved  on  to  the  pyloric  vestibule. 
By  observing  the  x-ray  shadows  cast  by  two  pellets  of  bismuth  subni- 
trate  it  has  been  noted  by  Cannon  that,  as  the  peristaltic  wave  approaches 


Fig.    157. — Section   of   the   frozen   stomach    (rat)    some   time   after    feeding   with   food    given    in    three 
differently   colored   portions.      (From   Howell's   Physiology.) 

a  pellet,  it  causes  it  to  move  forward  more  rapidly  for  a  short  distance, 
but  soon  overtakes  it  and  in  doing  so  causes  the  pellet  to  move  back  a 
little  towards  the  fundus.  This  backward  movement  is  less  than  the 
forward  movement,  so  that  after  the  Avave  has  passed,  the  position  of 
the  pellet  is  a  little  forward  of  that  which  it  would  have  occupied  had 
there  been  no  wave.  The  behavior  of  the  pellet,  and,  therefore,  of  the 
stomach  contents,  is  very  like  that  of  a  cork  floating  at  the  edge  of  the 
sea ;  as  each  wave  approaches,  it  hurries  the  cork  on  a  little,  but  after 
its  passage  the  cork  recedes  again  until  the  second  wave  carries  it  still 
a  little  farther  forward.  As  the  peristaltic  wave  approaches  the  pyloric 
vestibule  and  becomes  more  powerful  its  effect  on  the  pellets  becomes 
more  marked.  They  are  carried  rapidly  along  this  part  of  the  stomach, 
until  the  pylorus  is  reached.  If  this  remains  closed,  they  are  shot  back 
into  the  vestibule.  From  nine  to  twelve  minutes  may  elapse  before  they 
are  transferred  to  the  pylorus  from  the  place  where  they  are  first  affected 
by  the  peristaltic  wave. 


456  DIGESTION 

These  observations  made  on  eats  and  other  laboratory  animals  no 
doubt  also  apply  in  the  case  of  man.  Removal  of  the  contents  of  the 
cardiac  and  pyloric  regions  separately  with  a  stomach  tube  after  feeding 
with  a  test  meal  part  of  which  was  colored  with  carmine  or  charcoal, 
has  shown  that  none  of  the  coloring  material  was  present  in  the  contents 
of  the  pyloric  end  up  to  twenty  minutes  or  so  after  the  food  had  been 
taken.  It  then  appeared  but  at  first  only  in  traces.  Another  important 
distinction  between  the  food  in  the  two  portions  of  the  stomach  relates 
to  its  consistency.  In  the  pyloric  end  it  is  semifluid  and  homogeneous 
in  character;  in  the  cardiac  end,  on  the  other  hand,  it  is  a  lumpy,  rather 
incoherent  mass. 

The  gastric  movements  must  greatly  facilitate  the  digestive  processes 
in  the  stomach.  In  the  cardiac  part  the  undisturbed  condition  of  the 
food  will,  as  Ave  have  seen,  facilitate  the  digestive  action  of  ptyalin, 
whereas  in  the  body  of  the  stomach  the  peristaltic  waves,  besides  mov- 
ing the  food  onward,  will  tend  to  bring  fresh  portions  of  mucous  mem- 
brane and  food  in  contact,  so  that  the  latter  becomes  more  thoroughly 
mixed  with  the  pepsin  and  hydrochloric  acid.  In  the  pyloric  part,  where 
no  hydrochloric  acid  is  secreted,  the  contents,  already  sufficiently  acid 
in  reaction,  become  more  thoroughly  churned  up  with  the  local  pepsin 
secretion,  so  that  proteolytic  action  progresses  very  rapidly. 

The  peristaltic  Avaves  also  facilitate  absorption  from  the  stomach  of  such 
substances  as  glucose  in  concentrated  solution  and,  probably,  of  hydro- 
lyzed  protein:  Avater,  hoAvever,  is- not  absorbed.  One  effect  of  such 
absorption  is  the  production  of  gastrin,  A\-hich  Ave  have  seen  is  the  hor- 
mone concerned  in  maintaining  the  gastric  secretion  after  the  psychic 
floAv.  The  fact  that  the  mucosa  of  the  vestibule  has.  relatively  to  the 
cardiac  end,  feAv  secreting  glands  is  in  harmony  with  the  vieAV  that 
absorption  is  an  important  function  of  this  part  of  the  stomach. 

THE  EMPTYING  OF  THE  STOMACH 

The  Control  of  the  Pyloric  Sphincter 

When  digestion  has  proceeded  far  enough  in  the  stomach  to  bring  the 
food  into  a  homogeneous,  souplikc  fluid  ('chyme),  portions  of  this,  as  they 
are  driven  against  the  pyloric  sphincter  by  the  peristaltic  waves,  instead  of 
being  returned  as  an  axial  stream  into  the  stomach,  are  ejected  into  the 
duodenum. 

We  must  uoav  consider  the  mechanism  by  Avhich  the  pyloric  sphincter 
opens  to  permit  the  passage  of  the  chyme.  Bombardment  by  "the  peri- 
staltic Avaves  is  evidently  not  the  cause  of  its  opening,  for,  as  Ave  have 


THE    MECHANISMS   OF    DIGESTION  15*3 

seen,  many  such  waxes  may  arrive  at  it  without  tins  result.  Since  it  is 
evidently  in  order  thai  the  intestine  may  not  suddenly  become  over- 
whelmed with  large  masses  of  food  that  the  pylorus  only  occasionally 
opens,  it  mighl  be  thoughl  thai  its  opening  depends  upon  the  disten- 
tion of  the  upper  part  of  the  intestine  It  is  true  that  excessive  disten- 
tion of  the  upper  part  of  the  intestine  does  hold  the  pyloric  sphincter 
elosed,  but  this  can  not  be  the  physiologic  stimulus,  because  considerable 
quantities  of  chyme  are  never  found  here. 

The  first  clue  to  the  real  nature  of  the  mechanism  was  afforded  by 
observing  the  behavior  of  the  sphincter  when  solutions  are  introduced 
into  the  duodenum  through  a  fistula.  Acid  solutions  were  found  to 
cause  a  complete  inhibition  of  gastric  evacuation,  whereas  alkaline  solu- 
tions had  no  effect.  This  differenee  indicates  that  acids  in  contact  with 
the  duodenal  mucous  membrane  reflexly  excite  contraction  of  the  sphinc- 
ter, and  that  it  relaxes  only  after  the  aeid  has  become  neutralized 
by  mixing  with  the  pancreatic  juice  and  bile. 

On  aeeount  of  the  great  importance  of  the  pyloric  mechanism  in  insur- 
ing that  the  chyme  shall  enter  the  intestine  only  in  such  quantities  that 
it  can  be  properly  acted  upon  by  the  intestinal  digesting  juices,  it  will 
be  of  interest  to  consider  briefly  some  of  the  experimental  observations 
by  which  this  mechanism  has  been  studied.  We  may  consider  first  the 
evidence  that  acid  on  the  stomach  side  of  the  pylorus  causes  a  relaxation 
of  the  sphincter:  (I)  When  carbohydrate  food  is  fed,  it  ordinarily  leaves 
the  stomach  fairly  rapidly,  but  if  its  acid-absorbing  power  is  increased 
by  mixing  it  with  sodium  bicarbonate,  exit  from  the  stomach  is  greatly 
delayed.  (2)  Proteins  ordinarily  leave  the  stomach  more  slowly  than 
carbohydrates,  but  if  acid  proteins  are  fed,  their  exit  is  much  more 
rapid.  (3)  If  a  fistula  is  made  into  the  pyloric  vestibule  through  which 
some  of  the  contents  can  be  removed,  it  will  be  found  that  just  prior  to 
the  opening  of  the  pyloric  sphincter,  a  distinctly  acid  reaction  develops 
in  the  food;  and  furthermore  if  acid  solutions  are  injected  through  this 
fistula,  they  cause  the  pyloric  sphincter  to  open,  whereas  alkalies  retard 
its  opening.  (4)  A  similar  effect  of  acid  in  opening  the  sphincter  can 
be  demonstrated  by  applying  it  to  the  pyloric  mucosa  of  an  excised 
stomach  kept  alive  in  oxygenated  Ringer's  solution. 

The  evidence  that  acid  on  tlie  duodenal  side  causes  closure  of  the 
sphincter  is  as  follows:  (1)  When  acid  is  placed  in  the  duodenum  through 
a  fistula,  the  sphincter  will  not  open;  (2)  when  the  pancreatic  and  bile 
ducts  are  ligated,  the  stomach  empties  much  more  slowly  than  normally; 
and  (3)  the  discharge  of  protein  is  considerably  hastened  if  the  pylorus 
is  sutured  to  the  intestine  below  the  duodenum.  After  such  an  opera- 
tion it  was  observed  that  the  protein  began  to  leave  the  stomach  through 


458  DIGESTION 

the  pyloric  sphincter  about  the  same  time  as  normally,  but  the  subse- 
quent evacuation  Mas  very  much  accelerated,  because  no  acid  came  in 
contact  with  the  duodenal  mucosa.  Water  and  egg  Avhite  may  leave 
the  stomach  independently  of  any  acid  reflex  control  of  the  pylorus.  By 
observations  made  through  a  duodenal  fistula  it  has  been  found  that, 
after  a  quantity  of  water  has  been  swallowed,  most  if  not  all  of  it  very 
soon  enters  the  duodenum  in  a  more  or  less  continuous  stream.  It  is  no 
doubt  on  this  account  that  drinking  contaminated  water  is  especially 
dangerous  on  an  empty  stomach. 

The  nervous  pathway  through  which  these  acid  reflexes  take  place  has 
been  shown  to  be  the  myenteric  plexus.  Indeed,  the  whole  mechanism 
is  quite  analogous  with  that  which  we  shall  see  occurs  in  the  intestine 
during  peristalsis :  the  stimulus,  that  is,  the  acid,  causes  a  contraction 
of  the  gastric  tube  behind  it  and  a  dilatation  in  front. 


Fig.  158. — Outlines  of  shadows  in  abdomen  obtained  by  exposure  to  x-rays  2  hours  after 
feeding  with  food  containing  bismuth  subnitrate.  The  food  in  A  was  lean  beef,  and  in  B  boiled 
rice.  The  smaller  size  of  the  stomach  shadow  and  the  much  greater  total  area  of  the  intestinal 
shadows  in  B  than  in  A  show  that  carbohydrate  leaves  the  stomach  earlier  than  protein.  (From 
Cannon.) 

Rate  of  Emptying"  of  Stomach 

The  relationship  of  these  facts  to  the  rate  at  which  different  foodstuffs 
leave  the  stomach  is  very  readily  explained.  The  method  for  investigat- 
ing this  problem,  which  again  we  owe  to  Cannon,  consists  in  feeding  ani- 
mals with  a  strictly  uniform  amount  of  different  foods  made  up,  as 
nearly  as  possible,  of  equal  consistency  and  containing  bismuth  subni- 
trate in  the  proportion  of  5  gm.  to  each  25  c.c.  By  feeding  such  mix- 
tures to  cats  previously  starved  for  twenty-four  hours,  and  examining 
the  abdomen  by  the  x-ray  at  regular  intervals,  the  shadows  cast  by  the  food 
after  passage  into  the  intestine  can  be  outlined  on  tracing  paper,  and 
the  total  length*  measured  (Fig.  158).  In  taking  this  as  an  estimate  of 
the  amount  of  food  in  the  intestine,  several  errors  are  no  doubt  incurred 


*This  is  permissible  since  the  shadows  are  practically  all  of  the   same  width. 


T1IK     MECHANISMS    OK    DKiKSTION 


459 


on  account  of  the  crossing  and  foreshortening  of  the  loops,  etc.,  but,  as 
their  constancy  testifies,  there  is  no  doubt  that  the  results  are  sufficiently 
close  for  the  purpose  of  finding  out  how  quickly  food  gains  access  to  the 
small  intestine;  and  the  method  has  a  great  advantage  over  all  others 
in  that  digestion  is  allowed  to  proceed  practically  without  interruption. 
The  points  we  have  to  determine  are:  (1)  when  the  food  first  leaves  the 
stomach;  (2)  the  rate  at  which  different  foods  are  discharged;  (3)  the 
time  required  for  the  passage  through  the  small  intestine. 

Let  us  consider  first  of  all  the  results  obtained  by  feeding  with  prac- 
tically pure  fat  or  carbohydrate  or  protein.  By  plotting  the  length  of 
the  shadows  in  centimeters  along  the  ordinates,  with  hours  along  the 
abscissa},  curves  such  as  those  shown  in  Fig.  159  have  been  secured. 
When  fats  were  fed  (dash  line  in  chart),  the  discharge  began  rather 
slowly,  and  continued  at  a  slow  rate.  Even  after  seven  hours  some  fat 
still  remained  in  the  stomach,  and  at  no  time  was  any  large  quantity 


40 


30 


20 


10 


/ 

(^ 

' 

1 
1 

s 

s^f 

' 

^v 

pi 

//• 

0J-21  2  3  4  5  6  7 

Hours 

Fig.  159. — Curves  to  show  the  average  aggregate  length  of  the  food  masses  in  the_  small 
intestine  at  the  designated  intervals  after  feeding.  The  curve  for  various  fat  foods  is  in  the 
dash  line,  for  protein  foods  in  the  heavy  line,  and  for  carhohydratc  foods  in  the  light  line. 
(From    Cannon.) 

present  in  the  intestine,  indicating  that  almost  as  quickly  as  it  is  dis- 
charged into  this  part  of  the  gastrointestinal  tract  fat  becomes  digested 
and  absorbed.  The  discharge  of  carbohydrates  was  quite  different  (light 
line  in  chart)  ;  it  began  often  in  ten  minutes,  and  soon  became  abundant, 
reaching  a  maximum,  as  a  rule,  at  the  end  of  two  hours,  after  which  it 
fell  off,  the  stomach  being  empty  in  about  three  hours.  Protein  left  at  a 
rate  intermediate  between  that  for  fats  and  that  for  carbohydrates 
(heavjr  line).  Little  left  before  the  first  half  hour;  the  curve  then 
slowly  rose,  attaining  a  maximum  in  about  four  hours,  and  then  gradu- 
ally declining  at  about  the  same  rate  as  it  rose.  It  is  interesting  to  note 
that  at  the  end  of  half  an  hour  about  eight  times  as  much  carbohydrate 
had  left  the  stomach  as  protein;  at  the  end  of  an  hour,  five  times  as  much. 
These  results  are  clearly  dependent  upon  the  rates  at  which  the  dif- 
ferent foodstuffs  assume  an  acid  reaction  in  the  stomach.     Carbohydrate 


460  DIGESTION 

has  no  combining  power  for  acids,  so  that  the  acid  secreted  with  the 
psychic  juice  remains  uncombined  and  on  gaining- the  pyloric  vestibule 
excites  the  opening  of  the  sphincter.  Protein,  on  the  other  hand,  as  is 
well  known,  absorbs  considerable  quantities  of  free  hydrochloric  acid, 
so  that  for  some  considerable  time  after  it  is  taken,  none  of  the  acid  exists 
in  a  free  state.  Fats  owe  their  slow  discharge  partly  to  inhibition  of 
gastric  secretion,  and  partly  to  the  longer  time  it  takes  for  them  to  become 
neutralized  in  the  duodenum,  because  of  the  fatty  acid  split  off  by  the 
action  of  lipase. 

Interesting  observations  have  also  been  made  on  the  rate  of  discharge 
when  various  combinations  of  foodstuffs  were  fed.  This  has  been  done 
by  feeding  one  foodstuff  before  the  other,  or  by  mixing  the  foodstuffs. 
When  carbohydrates  were  fed  first  and  then  protein,  the  discharge  be- 
gan much  earlier  than  with  protein  alone,  because  the  carbohydrate  food 
first  reached  the  pyloric  vestibule  (see  page  454).  However,  at  the  end 
Of  two  hours,  when  the  carbohydrate  curve  should  begin  to  come  down,' 
it  remained  high,  indicating  that  the  protein  had  by  this  time  reached 
the  pylorus  and  was  being  discharged  at  its  own  rate.  When  the  meat 
was  fed  before  the  carbohydrate,  the  curve  to  start  Avith  was  exactly 
like  that  for  protein,  becoming,  however,  considerably  heightened  later 
when  the  carbohydrate  reached  the  pyloric  vestibule.  The  presence  of 
protein  near  the  pylorus,  therefore,  distinctly  retards  the  evacuation  of 
carbohydrate  from  the  stomach.  These  facts,  it  will  be  remarked,  all 
fit  in  admirably  with  the  observations  which  Ave  have  already  detailed 
concerning  the  disposition  of  food  in  the  stomach. 

When  mixtures  of  equal  parts  of  different  foods  were  fed,  the  results 
indicated  that  the  emptying  of  the  stomach  occurred  at  a  rate  which 
was  intermediate  between  those  of  the  foods  taken  separately.  Mixing 
protein  with  carbohydrate,  for  example,  accelerated  the  rate  at  which 
protein  left,  and  mixing  fats  with  protein  caused  the  protein  to  leave 
the  stomach  considerably  more  slowly  than  if  protein  alone  had 
been  fed. 

Influence  of  Pathologic  Conditions  on  the  Emptying 

An  important  surgical  application  of  these  facts  concerns  the  behavior 
of  food  after  gastroenterostomy.  It  has  been  thought  that  this  operation 
would  cause  the  food  to  be  drained  from  the  stomach  into  the  intestine 
and  thus  leave  the  region  of  the  stomach  between  the  fistula  and  the 
pylorus  inactive.  This  assumption  is  based  on  the  idea,  which  we  have 
seen  to  be  erroneous,  that  gravity  assists  in  the  emptying  of  the  stomach. 
As  a  matter  of  fact,  it  has  been  found  that,  if  the  gastroenterostomy  is 
made  when  there  is  no  obstruction  at  the  pylorus,  the  chyme  takes  its 


THE    MECHANISMS   OF    DIGESTION  46] 

normal  passage  through  the  sphincter  and,  almost  without  exception, 
none  leaves  by  the  fistula.  When  the  pylorus  is  partly  occluded,  the 
food  sometimes  passes  in  the  usual  way,  and  sometimes  by  the  stomach. 
The  cause  for  Ibis  predilection  for  the  pyloric  pathway  depends  on  the 
pressure  conditions  in  the  gastric  contents.  Gastroenterostomy,  there- 
fore, is  efficient  only  when  gross  mechanical  obstruction  exists  at  the 
pylorus.  The  operation  should  never  be  performed  in  the  absence  of 
demonstrable  organic  pyloric  disease. 

Another  objection  to  gastroenterostomy  in  the  presence  of  a  patulous 
pyloric  sphincter  rests  on  the  fact  that  the  food,  after  passing  the  sphinc- 
ter and  moving  along  the  intestine,  may  again  enter  the  stomach  through 
the  fistula.  This  is  most  likely  to  occur  when  the  stomach  is  full  of 
food,  for  under  these  conditions  the  stretching  of  its  walls  separates  the 
edges  of  the  opening,  the  intestine  being  draAvn  taut  between  the  edges, 
so  that  the  opening  between  the  stomach  and  the  intestine  assumes  the 
form  of  two  narrow  slits,  which  act  like  valves  permitting  the  food  to 
enter  but  preventing  its  escape  from  the  stomach.  Only  seldom  under 
these  circumstances  can  any  food  pass  into  the  intestine  beyond  the 
stomach  opening.  Repeated  vomiting  after  gastroenterostomy  has  been 
observed  in  experimental  animals  only  when  obstructive  kinks  or  other 
demonstrable  obstacles  were  present  in  the  gut,  the  obstruction  being  lo- 
cated in  that  part  of  the  intestine  beyond  its  attachment  to  the  stomach. 

When  the  pyloric  obstruction  is  complete,  food  must,  of  course,  leave 
by  the  fistula,  digestion  by  the  pancreatic  juice  and  bile  being  still  car- 
ried on  because  of  the  fact  that  for  a  considerable  distance  down  the 
intestine,  secretin,  which  we  have  seen  is  essential  for  the  secretion 
of  these  fluids,  is  still  produced  by  the  contact  of  the  acid  chyme  with 
the  intestinal  mucosa.  Further  provision  for  adequate  digestion  of 
food  in  such  cases  is-  secured,  as  some  of  the  food  after  leaving  the 
fistula  passes  back  for  some  distance  into  the  duodenum,  where,  however, 
it  soon  excites  peristaltic  waves,  which  again  carry  it  forward.  This 
insures  thorough  mixing  with  the  digestive  juices.  From  their  experi- 
mental experience  Cannon  and  Blake13  recommend  that,  when  the 
fistula  has  to  be  made,  it  should  be  as  large  as  possible  and  near  the 
pylorus,  and  that  the  stomach  afterwards  should  not  be  allowed  to 
become  filled  with  food.  To  avoid  kinking  of  the  gut,  they  also  recom- 
mend that  several  centimeters  of  the  intestine  should  be  attached  to  the 
stomach  distal  to  the  anastomosis. 

The  effect  of  hyperacidity  of  the  contents  on  the  emptying  of  the 
stomach  has  been  studied  by  feeding  animals  with  potatoes  containing 
varying  percentages  of  hydrochloric  acid.     With  an  acidity  of  0.25  per 


462  DIGESTION 

cent,  the  rate  of  discharge  was  increased,  but  it  became  slower  when  the 
acidity  rose  to  1  per  cent.  AVith  an  acidity  of  0.5  per  cent,  the  rate  of 
discharge  was  about  the  normal.  Hyperacidity,  therefore,  causes  a  retar- 
dation of  the  emptying  of  the  stomach. 

The  consistency  of  the  food  appears  to  have  little  influence  on  its  rate  of 
discharge  from  the  stomach — at  least  in  the  case  of  potatoes.  Dilution 
of  protein  food,  however,  increases  the  rate.  Distinctly  hard  particles 
in  the  food  retard  the  stomach  evacuation. 

There  is  usually  a  considerable  amount  of  gas  in  the  part  of  the  stomach 
above  the  entrance  of  the  cardia,  on  account  of  which  this  part  of  the 
stomach  has  sometimes  been  called  the  stomach  bladder.  In  the  upright 
position  this  gas  forms  a  bright  area  in  the  x-ray  plate  (Fig.  155),  but 
when  the  person  reclines  it  spreads  to  a  new  location.  Its  presence  may 
influence  gastric  digestion  by  preventing  the  contact  of  the  food  with 
the  mucous  membrane,  and  by  interfering  with  the  efficiency  of  the  peri- 
staltic waves  in  moving  the  food.  Considerable  gas  therefore  retards  the 
emptying  of  the  stomach,  as  has  been  shown  experimentally  by  x-ray 
observations  on  animals  fed  with  the  standard  amount  of  food  followed 
by  the  introduction  of  air.  It  was  noted  that  the  air  did  not  diminish 
the  frequency  or  strength  of  the  peristaltic  waves,  but  that  these  could 
not  efficiently  act  on  the  food.  When  along  with  gas  there  is  also  atony 
of  the  stomach  walls,  the  retardation  in  the  discharge  will,  of  course,  be 
still  more  pronounced.  The  temperature  of  the  swallowed  food  does 
not  appear  to  have  much  influence  on  the  stomach  movements  or  on  the 
the  rate  of  discharge  from  the  organ. 


CHAPTER  LIII 
THE  MECHANISMS  OF  DIGESTION   (Cont'd) 

THE  MOVEMENTS  OF  THE  INTESTINES 

The  length  of  the  small  intestine  and  the  size  of  the  cecum  of  the 
large  intestine  vary  considerably  in  different  animals.  In  the  carnivora, 
such  as  the  cat,  the  small  intestine  is  relatively  short ;  in  the  herbivora, 
relatively  long.  Thus,  it  is  three  times  the  length  of  the  body  in  the  cat, 
and  four  to  six  times  in  the  dog;  whereas  in  the  goat  and  sheep,  it  may 
be  nearly  thirty  times  the  length  of  the  body.  In  the  carnivora  the 
cecum  is  either  absent  or  rudimentary,  whereas  in  those  herbivora  which 
do  not  have  a  divided  stomach  the  cecum  is  very  large  and  sacculated, 
as  is  also  the  colon.  The  reason  for  the  great  size  in  herbivora  is  that 
practically  the  whole  of  the  digestion  of  cellulose  takes  place  in  this 
part  of  the  gut.  This  digestion,  as  we  shall  see  later,  does  not  depend 
on  any  secretion  poured  forth  by  the  animal  itself,  but  upon  the  action 
of  bacteria  and  of  certain  enzymes  (cytases)  that  are  taken  with  the 
vegetable  food. 

Movement  of  the  Small  Intestine 

The  movements  of  the  small  intestine  have  been  studied  (1)  by  the 
bismuth  subnitrate  and  x-ray  method,  (2)  by  observing  them  after  open- 
ing the  abdomen  of  an  animal  submerged  in  a  bath  of  physiologic  saline 
at  body  temperature,  (3)  by  observing  the  changes  in  pressure  produced 
in  a  thin-walled  rubber  balloon  inserted  in  the  lumen  of  the  gut  and 
connected  with  a  recording  tambour  (Fig.  160),  and  (4)  by  excising 
portions  of  the  intestine  and  keeping  them  alive  in  a  bath  of  saline  solu- 
tion at  body  temperature,  through  which,  oxygen  is  made  to  pass. 

The  Segmenting  Movements 

When  a  suitably  fed  animal  is  placed  on  the  holder  for  examination 
by  the  x-ray  method,  no  movement  in  the  intestinal  shadows  is  generally 
observed  for  some  time.  The  first  movement  to  appear  is  the  breaking  of 
one  of  the  columns  of  food  into  small  segments  of  nearly  equal  size. 
Each  of  these  segments  again  quickly  divides,  and  the  neighboring 
halves  suddenly  unite  to  form  new  segments,  and  so  on,  in  a  manner 

463 


464 


DIGESTION 


which  will  be  made  clear  by  consulting  Fig.  161.  This  rhythmic  seg- 
mentation, as  Cannon  has  called  it,  continues  without  cessation  for  more 
than  half  an  hour,  and  the  food  shadow  does  not  meanwhile  seem  to  change 
its  position  in  the  abdomen  to  any  extent.  The  splitting  up  of  the  seg- 
ment and  the  rushing  together  of  the  neighboring  halves  proceed  as  a 
rule  with  great  rapidity;  thus,  if  we  count  the  number  of  different  seg- 


I'"ig.    160. — Apparatus    for    recording    contractions*  of    the    intestine.       (From    Jackson.) 


ments  during  a  definite  period,  we  may  find  the  rate  of  division  in  the 
cat  to  be  as  high  as  28  or  30  a  minute.  In  man  the  divisions  occur  at  a 
frequency  of  approximately  10  per  minute,  which  corresponds  to  the  fre- 
quency with  which  sounds  can  be  heard  when  the  abdomen  is  auscultated. 
Although  half  an  hour  is  the  period  which  this  process  usually  oc- 
cupies, it  may  last  considerably  longer.  In  certain  animals,  such  as  the 
rabbit,    segmenting    movements    have    not    been    observed,    but     instead 


THE    MECHANISMS   OF    DIGESTION  465 

of  them  a  rhythmic  to-and-fro  shifting  of  the  masses  of  food  along  the 
lumen  of  the  gut,  rapidly  repeated  for  many  minutes. 

When  the  intestines  are  floated  out  in  .1  warm  bath  of  saline  solution, 
it  is  seen  that  the  rhythmic  segmentation  is  caused  by  narrow  rings  of 
contraction.     Under   such   conditions  also   it   is   often    noted   that  the 

loops  of  intestine  sway  Erom  side  to  side.  The  balloon  method  also  re- 
veals the  presence  of  slight  waves  of  contraction  that  pass  rapidly  along 
the  gut,  and  follow  each  other  at  the  rate  of  twelve  to  thirteen  per  minute. 
Both  of  the  muscular  coats  of  the  intestine  are  involved,  and  it  is  believed 
that  the  contractions  are  responsible  not  only  for  the  pendular  move- 
ments but  for  the  rhythmic  segmentation  observed  by  the  x-ray  method. 
According  to  this  view  these  movements  are  constantly  passing  along 
the  intestine,  and  become  exaggerated  by  the  mechanical  stimulus  which 
is  offered  by  the  masses  of  food  to  such  an  extent  that  they  divide  the 
masses  into  portions.     The  evidence,  for  this  belief  rests  on  the  fact  that 


•  cD<R&8$B&rf> 


Fig.  161. — Diagrammatic  representation  of  the  process  of  segmentation  in  the  intestine.  An 
unbroken  shadow  is  shown  in  /  and  its  segmentation  in  2.  The  dotted  lines  across  each  mass 
show  the  position  of  division  and  in  3  is  shown  how  new  masses  are  formed  by  the  split  portions 
coming   together.      (.From    Cannon.) 

when  the  contraction  is  studied  by  the  balloon  method,  it  becomes  marked 
over  the  middle  of  the  balloon,  where  the  greatest  tension  exists. 

Several  functions  can  be  assigned  to  these  movements.  They  cause 
intimate  mixture  of  the  food  with  the  digestive  juices,  and  by  bringing 
ever  new  portions  of  food  in  contact  with  the  mucosa,  they  encourage 
absorption.  They  also  have  an  important  massaging  influence  on  the 
blood  and  lymph  in  the  vessels  of  the  intestinal  walls.  Indeed,  the  pas- 
sage of  lymph  from  the  lacteals  into  the  mesenteric  lymphatics  seems  to 
depend  very  largely  upon  these  movements. 

The  Peristaltic  Movements 

The  other  movement  observed  in  the  small  intestine  is  that  known  as  the 
peristaltic  wave.  It  occurs  in  two  forms:  (1)  as  a  slowly  advancing  con- 
traction (1  to  2  cm.  per  minute),  preceded  by  an  inhibition  of  the  walls, 
and  proceeding  only  through  a  short  distance  in  a  coil  (4  to  5  cm.);  and 


466 


DIGESTION 


(2)  as  a  swift  movement  called  the  peristaltic  rush,  which  sweeps  with- 
out pause  for  much  longer  distances  along  the  canal. 

Further  analysis  of  the  peristaltic  wave  can  readily  be  made  by  the 
balloon  method  (Fig.  162).  If  the  gut  is  pinched  above  the  balloon,  a 
marked  relaxation  occurs  over  it,  and  this  relaxation  extends  for  about 
two  feet  down  the  intestine.  If.  on  the  other  hand,  the  gut  is  pinched 
a  little  below  the  situation  of  the  balloon,  a  long-continued  contraction 
occurs  over  the  latter.  The  conclusion  that  we  may  draw  from  this  result 
is  that  the  stimulation  of  the  gut  causes  contraction  above  the  point  of. 
the  stimulus  and  relaxation  below,  this  being  known  as  "the  law  of  the 
intestine" — (Bayliss  and  Starling).  "We  have  seen  that  it  applies  also  in 
the  case  of  the  cardiac  and  pyloric  sphincters. 


Fig.  162. — Intestinal  contractions  f  balloon  method)  after  excision  of  the  abdominal  ganglia  and 
section  of  both  vagi.  Mechanical  stimulation  above  (/)  and  below  O)  the  balloon  causes  relaxa- 
tion  and   contraction    respectively.      (From    Starling.) 


The  Physiologic  Nature  of  the  Rhythmic  and  Peristaltic  Movements 

Interesting  information  in  this  connection  has  been  gained  by  obser- 
vation of  the  behavior  of  the  movements  after  the  application  of  drugs 
to  the  gut  or  after  cutting  the  nerve  supply.  The  rhythmic  movements 
are  not  affected  by  the  application  of  nicotine  or  cocaine.  Since  these 
drugs  paralyze  nervous  structures  it  has  been  concluded  that  the  rhythmic 
movements  are  myogenic  in  origin.  The  question  is  not  a  settled  one, 
however,  for  it  has  been  found  by  Magnus  that,  although  strips  of  the 
longitudinal  muscle,  isolated  in  oxygenated  saline  solution,  will  continue 
to  beat,  they  do  not  do  so  if  the  adherent  Auerbaclrs  plexus  of  nerves 
is  stripped  off  from  them.  The  nature  of  the  peristaltic  contractions  is 
more  definite ;  they  must  clearly  depend  upon  a  local  nervous  struc- 
ture, since  they  are  paralyzed  by  the  application  to  the  gut  of  cocaine  or 
nicotine.  This  local  nervous  system  no  doubt  also  resides  in  Auerbach's 
plexus,  which  must  therefore  be  considered  as  complex  enough  to  be  (see 


THE    MECHANISMS   OP    DIGESTION  467 

page  796)  endowed  with  the  power  of  directing  nervous  impulses  so  as  to 
l>riii'.:  about  relaxation  of  the  gu1  in  front  of  ili<-  stimulus  and  contrac- 
tion over  it. 

Nervous  Control  op  Movements 

The  influence  of  the  central  nervous  system  on  the  intestinal  movements 
has  been  studied  by  the  usual  methods  of  cutting  and  stimulating  the 
extrinsic  nerve  supply.  Through  the  splanchnic  nerves  tonic  inhibitory 
impulses  are  conveyed  to  the  intestine  (except  the  ileocolic  sphincter), 
for  after  these  nerves  are  severed  the  movements  become  more  distinct. 
Indeed,  in  many  animals  after  opening  the  abdomen  no  intestinal  move- 
ment can  be  observed  until  these  nerves  have  been  cut.  Stimulation  of  the 
peripheral  end  of  the  nerve  also  inhibits  any  movement  which  may  mean- 
while be  in  progress.     The  impulses  through  the  vagus  nerve  are  of  an 


Fig.    Ki3. — The  effect  of  excitation  of  both   splanchnic   nerves  on   the   intestinal  contractions.      (From 

Starling.) 

opposite  character.  Section  of  these  nerves  has  little  effect,  but  stimula- 
tion causes  contraction.     (Figs.  163  and  164.) 

By  observing  the  rhythmic  contractions  of  an  isolated  strip  of  the  small 
intestine  suspended  in  a  bath  of  oxygenated  saline  solution  at  body  tem- 
perature, it  can  readily  be  shown  that  the  presence  of  even  a  minute  trace 
of  epinephrine  is  sufficient  to  produce  complete  inhibition  of  the  movement. 
The  parallelism  between  the  effects  of  splanchnic  stimulation  and  those  of 
epinephrine  injection  is  very  significant,  for  in  this  way  the  marked  inhi- 
bition of  intestinal  movement  which  occurs  during  fright  may  possibly 
be  explained   (see  page  736). 

The  circular  muscular  coat  of  the  last  two  or  three  centimenters  of 
the  ileum  before  it  joins  the  cecum  is  definitely  thicker  than  the  rest  of 
this  coat,  indicating  that  it  has  a  sphincter-like  action.  This  ileocolic 
sphincter,  as  it  is  called,  opens  when  food  is  pressed  against  it  from  the 
ileum,  but  remains  closed  when  food  is  pressed  against  it  from  the  cecum. 


468 


mOESTION 


It  therefore  obeys  the  law  of  the  intestine.  That  it  is  physiologically 
distinct  from  the  musculature  of  the  rest  of  the  ileum  is  indicated  by  the 
fact  that  the  splanchnic  and  vagus  nerves  do  not  affect  it  in  the  same 
way;  thus,  stimulation  of  the  splanchnic  causes  a  strong  contraction  of 
the  sphincter,  whereas  it  is  unaffected  by  stimulation  of  the  vagus. 

Peristalsis  is  much  more  rapid  in  the  duodenum  than  in  other  parts  of 
the  small  intestine.  During  the  first  stages  of  digestion,  the  food  ordi- 
narily lies  mainly  in  the  right  half  of  the  abdomen,  and  later  in  the  left 
half.  There  is  considerable  variation  in  the  time  that  elapses  before  it 
enters  the  colon.  In  the  cat,  carbohydrates  reach  this  part  of  the  gut  in 
about  four  hours. 


•Jl 


{vx.v**.  ce 


rmwwm        i— i  i— — — i 

Fig.    164. — The    effect    of   stimulation    of   right    vagus    nerve    on    the    intestinal    contractions.       (From 

Starling.) 

Movements  of  the  Large  Intestine 

On  account  of  the  great  differences  which  we  have  already  seen  to 
exist  in  the  size  and  relative  importance  of  the  colon  as  a  digestive  organ 
in  different  classes  of  animals,  it  is  not  surprising  that  the  movements 
observed  are  very  different  according  to  the  dietetic  habits  of  the  animal. 
Apparently  the  movements  are  much  the  same  in  the  cat  as  in  man.  As 
the  food  passes  through  the  ileocolic  sphincter  into  the  cecum  and 
accumulates  there,  it  gradually  sets  up,  by  its  pressure,  a  contraction  of 
the  muscular  walls  of  the  gut  somewhere  about  the  junction  between 
the  ascending  and  transverse  colon.  This  wave  of  contraction  then 
begins  to  travel  slowly  toward  the  cecum,  without,  however,  being  pre- 
ceded by  any  relaxation  of  the  wall  of  the  gut,  as  is  the  case  with  a  true 


THE    MECHANISMS   OF    DIGESTION 


Ki'l 


peristaltic  wave.  This  first  wave  is  soon  followed  by  others,  with  the 
result  thai  the  food  is  forced  up  into  the  cecum,  againsl  the  blind  end 
of  which  it  is  crowded,  being  meanwhile  prevented  from  passing  into 
the  ileum  by  the  operation  of  the  ileocolic  sphincter  and  by  the  oblique 
manner  in  which  the  ileum  opens  into  the  cecum. 

As  the  result  of  the  distention  of  the  cecum  set  up  by  these  so-called 
antiperistaltic  waves,  a  true  coordinated  peristaltic  wave  is  occasionally 
initialed,  and  passes  along  the  ascending  colon  preceded  by  the  usual 
wave  of  inhibition.  These  waves,  however,  disappear  before  they  reach 
the  end  of  the  colon,  so  that  the  food  is  again  driven  back  by  the  so- 


Fig.    165. — Diagram    of    time    it   takes    for    a    capsule    containing    bismuth    to    reach    the    various    parts 

of   the   large    intestine. 

called,  antiperistaltic  waves.  The  effect  of  the  movements  is  to  knead 
and  mix  the  intestinal  contents,  and  thus  encourage  the  absorption  of 
water  from  them.  The  resulting  more  solid  portions  then  collect  toward 
the  splenic  flexure,  and  become  separated  from  the  remaining  more  fluid 
portion  by  transverse  waves  of  constriction,  which  develop  into  peri- 
staltic waves  carrying  the  harder  masses  into  the  distal  portions  of  the 
colon,  where  they  collect  chiefly  in  the  sigmoid  flexure.  The  descending 
colon  itself  is  never  distended  with  contents  and  merely  serves  as  a  tube 
for  transferring  the  masses  from  the  transverse  colon  to  the  sigmoid 
flexure.  The  time  taken  for  a  capsule  of  bismuth  to  reach  the  various 
parts  of  the  large  intestine  is  shown  in  Fig.  165. 

After  a  certain  mass  has  collected  in  the  sigmoid  flexure  and  rectum, 
the  increasing  distention  causes  a  reflex  evacuation  of  this  portion  of  the 


470  DIGESTION 

gut  through  centers  located  in  the  spinal  cord.  The  impulses  from  these 
centers,  besides  contracting  the  rectum,  etc.,  also  coordinate  the  contrac- 
tion of  the  abdominal  muscles  and  the  relaxation  of  the  sphincter  ani 
so  as  to  bring  about  the  act  of  defecation.  By  the  skiagraphic  method  it 
has  been  found  that  the  pelvic  colon  gradually  becomes  tilled  "with  feces 
from  below  upward,  and  that  the  rectum  remains  empty  until  just  before 
defecation. 

Effect  of  Clinical  Conditions  on  the  Movements 

Observations  of  practical  value  have  been  made  on  the  behavior  of  the 
peristaltic  wave  after  various  intestinal  operations.  After  an  end-to-end 
anastomosis  of  the  gut,  no  evidence  can  be  obtained  by  the  x-ray  method 
that  any  hesitation  occurs  in  the  movement  of  the  shadows  at  the  anas- 
tomosis. On  the  other  hand,  when  a  lateral  anastomosis  is  established, 
stagnation  of  the  food  in  the  region  of  the  junction  may  occur,  this 
having  been  found,  on  opening  the  gut,  to  be  caused  by  the  accumu- 
lation of  hair  and  undigested  detritus  at  the  opening  between  the  op- 
posed loops.  Another  objection  to  lateral  anastomosis  is  the  fact  that 
in  performing  the  operation  a  considerable  amount  of  the  circular  muscle 
is  cut.  which  interferes  with  peristaltic  activity.  Moreover,  the  end  of 
the  proximal  loop  beyond  the  opening  is  in  danger  of  becoming  filled  up 
with  hardened  material,  and  the  end  of  the  distal  loop  may  become 
invaginated  and  induce   obstruction  in  the  region   of  the   anastomosis. 

Observations  have  also  been  made  by  the  x-ray  method  on  the  be- 
havior of  the  intestinal  contents  following  intestinal  obstruction.  It  has 
been  observed  that,  as  the  material  collects  in  the  gut  just  above  the 
obstruction,  strong  peristaltic  waves  are  set  up,  which  move  the  food 
toward  the  obstruction  so  powerfully  as  to  cause  the  walls  of  the  canal 
in  front  to  become  bulged,  until  at  last  the  pressure  causes  the  con- 
tents to  be  squirted  back  through  the  advancing  ring  of  peristaltic  con- 
traction. These  waves  were  observed  to  succeed  one  another  rapidly. 
"When  a  portion  of  gut  is  reversed  in  position,  the  peristaltic  waves  con- 
tinue to  travel  in  their  old  direction  toward  the  duodenum.  The  effect  of 
this  is  to  produce  a  partial  obstruction  at  the  upper  end  of  the  re- 
ceptive gut. 

The  type  of  peristalsis  known  as  the  peristaltic  rush  can  be  induced 
experimentally  in  animals  by  intravenous  injection  of  ergot.  It  prob- 
ably also  occurs  in  conditions  of  abnormal  irritation  of  the  gut  in  man, 
and  is  believed  to  be  the  characteristic  activity  of  the  gut  after  a 
strong  purge. 


CHAPTER  LIV 
HUNGER  AND  APPETITK 

Bunger  and  appetite  are  distinct  sensations,  the  former  being  definitely- 
correlated  with  contraction  of  the  empty  stomach,  and  the  latter  being 
a  complex  of  sensations  operating  in  the  nervous  system  along  with 
memory  impressions  of  the  sight,  taste,  and  smell  of  palatable  food. 
Appetite  is  therefore  a  highly  complex  nervous  integration,  whereas 
hunger  is  a  much  simpler  process.  It  is  particularly  with  hunger  that 
Ave  shall  concern  ourselves  at  present. 

When  a  thin-walled  rubber  balloon  of  proper  size  is  placed  in  the 
stomach  and  connected  by  a  rubber  tube  with  a  water,  bromoform  or 
chloroform  manometer  (made  of  wide  glass  tubing  1.5  cm.  in  diameter 
and  provided  with  a  suitable  float  on  the  free  limb)  a  tracing  may  be 
taken  of  the  movements  of  the  stomach.  For  use  on  man  the  capacity  of 
the  balloon  should  be  from  75  to  150  cubic  centimeters.  The  record  thus 
obtained  when  the  balloon  is  placed  in  the  empty  stomach  of  a  normal 
person  shows  four  types  of  wave.  Two  of  these  may  be  discounted, 
being  due  to  the  arterial  pulse  and  the  respiratory  movements.  The 
third  is  known  as  the  tonus  rhythm,  and  is  caused  by  tonic  contractions 
of  the  fundus  of  the  stomach  of  varying  amplitudes  and  occurring  at  a 
rate  which  varies  from  18  to  22  per  second.  The  periods  of  tonus  in- 
crease during  the  powerful  rhythmic  contraction  to  be  immediately 
described.  While  these  changes  in  tone  are  occurring,  no  subjective  sen- 
sation of  hunger  is  experienced.     (See  Fig.  167.) 

The  fourth  and  most  significant  type  consists  of  powerful  rhythmic 
contractions,  alternating  with  periods  of  quiescence.  These  contrac- 
tions occupy  a  period  of  about  twenty  seconds,  and  are  superimposed 
upon  the  tonus  rhythm.  They  gradually  increase  in  amplitude  and  fre- 
quency; and,  in  the  case  of  young  and  vigorous  persons,  may  gradually 
pass  into  a  condition  of  incomplete  tetanus,  after  which  they  suddenly 
subside,  leaving  only  a  faint  tonus  rhythm.  These  rhythmic  contrac- 
tions are  definitely  associated  with  the  sensation  of  hunger,  and  are 
more  marked  the  more  intense  the  sensation  is.  When  tetanus  occurs 
the  hunger  sensation  is  continuous,  but  it  instantly  disappears  when 
the  tetanus  gives  place  to  relaxation.  When  the  contractions  are  com- 
paratively feeble,  the  length  of  the  period  during  which  they  occur  is 

471 


472 


DIGESTION 


about  twelve  minutes,  being  shorter  than  when  the  contractions  are  power- 
ful, in  which  case  the  periods  are  always  initiated  by  weaker  contrac- 
tions with  long  intervening  pauses.  Finally,  the  pauses  disappear  and 
the  contractions  become  more  and  more  pronounced  until,  as  above  men- 
tioned, a  virtual  tetanus,  lasting  from  two  to  five  minutes,  may  super- 
vene. The  duration  of  the  hunger  period  varies  from  one-half  to  one  and 
a  half  hours,  with  an  average  of  from  thirty  to  forty-five  minutes,  and 
the  number  of  individual  contractions  in  a  period  varies  from  twenty  to 
seventy.  Between  the  hunger  periods,  intervals  of  from  one-half  to 
two  and  one-half  hours  of  quiescence  may  supervene.     (See  Fig.  168.) 

Similar  contractions,  often  passing  into  incomplete  tetanus,  have  been 
observed  in  the  stomach  of  healthy  infants,  some  of  the  observations  hav- 
ing been  made  before  the  first  nursing.     The  intervals  of  motor  quies- 


Fig.  166.— -Diagram  of  method  for  recording  stomach  movements.  B,  rubber  balloon  in  stomach. 
D,  kymograph.  F,  cork  float  with  recording  flag.  M,  manometer.  L,  manometer  fluid  (bromo- 
form,  chloroform,  or  water).  R,  rubber  tube  connecting  balloon  with  manometer.  S,  stomach. 
T,   side   tube   for   inflation   of   stomach    balloon.      (From   Carlson.) 


cence  between  the  hunger  periods  are  shorter  than  in  adults.  In  obser- 
vations made  during  sleep,  it  was  observed  that,  when  the  contractions 
were  very  vigorous,  the  infant  would  show  signs  of  restlessness  and 
might  awake  and  cry.  As  in  the  adult,  the  contractions  are  evidently 
associated  with  subjective  sensations  of  hunger.  Contractions  of  the 
empty  stomach  have  also  been  recorded  on  a  large  variety  of  animals, 
including  the  dog,  rabbit,  cat,  guinea  pig,  bird,  frog  and  turtle.  They 
vary  somewhat  in  type  in  different  animals. 

With  regard  to  the  time  of  onset  of  the  tonus  and  hunger  contractions, 
it  has  been  observed  that  the  only  period  during  which  the  fundus  is 
free  of  them  is  immediately  after  a  large  meal.  After  a  moderate  meal 
the  tonus  rhythm  begins  to  appear  in  about  thirty  minutes.    It  gradually 


HUNGER    AND    APPETITE  47o 

increases  in  Intensity,  until  by  the  time  the  stomach  has  nearly  emptied 
itself  the  tonus  has  become  conspicuous,  and  the  stronger  hunger  eon- 
tractions  usually  begin  to  appear.  Superimposed  upon  those  of  the 
tonus  rhythm,  hunger  pangs  may  appear  in  man  irlioi  the  stomach  still 
contains  traces  of  food. 


Pig.    167. — Tracing  of   the   tonus   rhythm   of   the  stomach    (man)    three   hours   after   a   meal.      (From 

Carlson.) 

By  studying  the  shadow  of  the  outline  of  the  stomach  produced  by 
having  a  person  or  animal  swallow  two  balloons,  one  inside  the  other 
and  with  a  paste  of  bismuth  subnitrate  between  them,  it  has  been  ob- 
served that  the   weaker  type   of  hunger  contraction   begins   as   a   con- 


Fig.   168. — Tracings  from  the  stomach  during  the  culmination  of  a  period  of  vigorous  gastric  hunger 
contractions.      One-half    original    size.      (From    Carlson.) 

strict  ion  involving  the  cardiac  end  of  the  stomach,  and  moving  toward 
the  pyloric  end  as  a  rapid  peristaltic  wave.  When  the  contractions  are 
very  vigorous,  this  wave  spreads  so  rapidly  over  the  stomach  that  it  is 
difficult  to  determine  whether  it  really  occurs  as  a  very  rapid  peristalsis 
or  as  a  contraction  involving  the  fundus  as  a  whole.    These  contractions 


474  DIGESTION 

resemble  very  closely  the  movements  that  have  sometimes  been  observed 
after  a  bismuth  meal,  and  which  have  been  thought  by  clinical  observers 
to  indicate  a  hyperperistalsis  of  the  stomach.  The  fundus  is  therefore 
not  entirely  passive  during  digestion ;  for,  although  early  in  this  act 
there  may  be  no  evidence  of  contraction,  yet  the  contractions  of  the  tonus 
rhythm  may  appear  and  become  pronounced  before  the  stomach  is  en- 
tirely empty.  In  other  words,  the  digestion  contractions  of  the  filled 
stomach  (see  page  451)  pass  gradually  over  into  the  hunger  contractions 
of  the  empty  organ. 

It  appears  that  the  stomach  contractions  produce  the  hunger  sensa- 
tions by  causing  stimulation  of  afferent  nerve  endings  in  the  muscle 
layers  of  the  viscus.  Mere  pressure  on  the  mucosa  itself  does  not  originate  ■ 
such  a  sensation;  thus,  sudden  distention  of  the  balloon  or  rubbing  the 
mucosa  with  the  closed  end  of  a  test  tube,  inserted  through  a  gastric 
fistula,  did  not  cause  any  sensation  of  hunger,  unless  the  stimulus  was 
so  strong  as  to  cause  a  contraction  of  the  musculature  of  the  stomach. 

It  has  been  thought  by  some  observers  that,  during  hunger,  contrac- 
tions similar  to  those  of  the  stomach  also  occur  in  the  lower  end  of  the 
esophagus.  It  is  believed  by  Carlson,  however,  that  these  contractions 
are  not  at  all  responsible  for  the  hunger  sensation,  although  they  may 
give  rise  to  a  feeling  that  something  has  stuck  in  the  esophagus.  Con- 
tractions of  the  intestine  have  also  been  observed  in  hunger,  but  it  is  doubt- 
ful whether  they  have  anything  to  do  with  the  cause  of  the  hunger 
sensation. 

REMOTE  EFFECTS  OF  HUNGER  CONTRACTIONS 

It  is  well  known  that  during  hunger  certain  general  subjective  symp- 
toms are  likely  to  be  experienced,  such  as  a  feeling  of  weakness  and  a 
sense  of  emptiness,  with  a  tendency  to  headache  and  sometimes  even 
nausea  in  persons  who  are  prone  to  headache  as  a  result  of  toxemic 
conditions.  Headache  is  likely  to  be  more  pronounced  or  perhaps  only 
present  in  the  morning  before  there  is  any  food  in  the  stomach.  These 
symptoms  indicate  that  hunger  contractions  are  associated  Avith  hyper- 
excitability  of  the  central  nervous  system,  "and  it  is  of  considerable 
interest  that  objective  signs  of  this  association  can  be  elicited.  If  the 
knee-jerk  be  recorded  along  with  a  record  of  the  gastric  contractions,  it 
will  be  found  that  it  is  markedly  exaggerated  simultaneously  with  the 
strong  hunger  contractions  of  the  empty  stomach,  this  augmentation 
being  greatest  at  the  height  of  the  stomach  contractions,  when  the  hun- 
ger pangs  are  most  intense,  and  falling  off  again  to  normal  when  these 
disappear   (Fig.   169).     Further  changes   occurring   during  the   hunger 


HUNGER    AND    APPETITE 


475 


period  include  an  increase  in  the  pulse  rate  and  vasodilatation.  By 
comparing  plethysmography  tracings  of  the  arm  volume  (see  page  230) 
and  stomach  contractions,  it  has  been  found  thai  the  increase  in  volume 
occurs  pari  passu  with  the  increasing  tonus  of  the  stomach,  but  that  it 
begins  to  shrink  before  the  stomach  contraction  lias  reached  its  maximum. 
Occasionally,  however,  as  in  acute  hunger,  a  somewhat  different  rela- 
tionship obtains,  vasoconstriction  being  more  prominent.  During  each 
hunger  contraction  there  is  also  increased  salivation,  the  degree  of 
which  varies  with  different  individuals.  This  salivation  is  independent 
of  the  more  copious  "watering  of  the  mouth"  that  accompanies  the 
thought  or  sight  of  appetizing  food. 


n 


L_U 


-U 


tmrrmtrrtttrrtmttttttfrrtr 


•tttttttttttttttttttttttintttttttimmititiithmitttti 


Fig.    169. — Showing   augmentation   of   the   knee-jerk    (upper  tracing)    during   the   marked   hunger    con- 
tractions   (lower    tracing).      (From    Carlson.) 


HUNGER  DURING  STARVATION 

During  enforced  starvation  for  long  periods  of  time,  it  is  known 
that  healthy  individuals  at  first  experience  intense  sensations  of  hunger 
and  appetite,  which  last  however  only  for  a  few  days,  then  become  less 
pronounced  and  finally  almost  disappear.  It  is  of  interest  to  know  the 
relationship  between  these  sensations  and  the  hunger  contractions  in 
the  stomach.  This  has  been  investigated  by  Carlson  and  Luckhardt,  who 
voluntarily  subjected  themselves  to  complete  starvation,  except  for  the 
taking  of  water,  for  four  days.  During  a  great  part  of  this  time  records 
of  the  stomach  contractions  were  taken  by  the  balloon  method,  and  it 
was  found  that  the  tonus  of  the  stomach  and  also  the  frequency  and 
intensity  of  the  hunger  contractions  became  progressively  more  pronounced 
as  starvation  proceeded.  Towards  the  end  of  the  period  it  was  also  noted 
that  incomplete  hunger  tetanus  made  its  appearance  where  ordinarily, 
as  in  Carlson's  case,  this  type  of  hunger  contraction  Avas  infrequent. 
Sensations  of  hunger  were  present  more  or  less  throughout  the  period, 
being  therefore  probably  due  to  the  persistently  increased  tonus.  The 
onset  of  a  period  of  hunger  contraction  could  usually  be  foretold  by  an 


476  DIGESTION 

increase  in  the  hunger  sensation,  and  as  these  contractions  became  more 
marked,  the  hunger  sensations  became  more  intense.  On  the  last  day  of 
starvation  a  burning  sensation  referred  to  the  epigastrium  was  added  to 
that  of  hunger.  The  appetite  ran  practically  parallel  with  the  sensa- 
tion of  hunger,  and  both  of  these  sensations  became  perceptibly  dimin- 
ished on  the  fourth  or  last  day  of  starvation,  this  diminution  being, 
however,  most  marked  in  the  sensation  of  appetite.  Indeed,  instead  of  an 
eagerness  for  food,  there  developed  on  the  last  day  a  distinct  repugnance 
or  indifference  towards  it.  Accompanying  these  sensations  of  hunger 
and  appetite  a  distinct  mental  depression  and  a  feeling  of  weakness  were 
experienced  during  the  latter  part  of  the  starvation  period. 

On  partaking  of  food  again  the  hunger  and  appetite  sensations  very 
rapidly  disappeared,  and  also  practically  all  of  the  mental  depression 
and  a  great  part  of  the  feeling  of  weakness.  Complete  recovery  from 
the  latter,  however,  did  not  take  place  until  the  second  or  third  day 
after  breaking  the  fast,  From  this  time  on  both  men  felt  unusually 
well';  indeed  they  state  that  their  sense  of  well-being  and  clearness  of 
mind  and  their  sense  of  good  health  and  vigor  were  as  greatly  improved 
as  they  would  have  been  by  a  month's  vacation  in  the  mountains.  They 
further  point  out  that,  since  others  who  have  starved  for  longer  periods 
of  time  unanimously  attest  the  fact  that,  after  the  first  few  days,  the 
sensations  of  hunger  become  less  pronounced  and  finally  almost  dis- 
appear, they  must  have  experienced  the  most  distressing  period  during 
their  four  days  of  starvation.  Although  the  hunger  sensation  was 
strong  enough  to  cause  some  discomfort,  it  could  by  no  means  be  called 
marked  pain  or  suffering,  and  was  at  no  time  of  sufficient  intensity  to 
interfere  seriously  with  work.  Mere  starvation  can  not  therefore  be 
designated  as  acute  suffering,  ft  is  of  further  interest  to  note  that  dur- 
ing the  starvation  period  a  continuous  (low  of  secretion  of  acid  gastric 
juice  was  found  to  occur  in  the  stomach,  the  presence  of  this  acid  prob- 
ably explaining  the  acid  or  burning  sensation  experienced  in  the  epigas- 
trium on  the  last  days. 

CONTROL  OF  THE  HUNGER  MECHANISM 

The  control  of  the  hunger  mechanism,  like  that  of  any  other  mechan- 
ism in  the  animal  body,  may  be  effected  through  the  nervous  system  or 
it  may  depend  on  the  presence  of  chemical  substances  or  hormones  in 
the  blood.  As  a  matter  of  fact,  it  can  readily  be  shown  that  both  those 
methods  of  control  are  operative,  and  Ave  will  now  consider  briefly  some 
of  the  facts  upon  which  this  conclusion  depends. 

Although  many  facts  are  now  known  with  regard  to  the  nervous  con- 


HUNGER    \\'l>    AI'l'l.TlTi  477 

trol  of  the  hunger  mechanism,  ii   is  difficult  l<>  piece  those  together  in 

such  a  way  as  to  formulate  a  simple  theory  which  fits  in  with  all  the 
observed    facts.      We   know    that    the   stomach    possesses    iii    itself   a   local 

nervous  mechanism  by  which,  like  -the  heart  or  intestine,  it  can  auto- 
matically perform  many  of  the  movements  which  are  exhibited  in  the 

intact  animal.  '  These  local  movements  may,  however,  be  considerably 
influenced  by  impulses  transmitted  to  the  stomach  along  the  vagus  and 
splanchnic  nerves.  We  have  therefore  to  seek  for  evidence  indicating 
the  relative  importance  of  the  local  nervous  mechanism  in  the  stomach 
itself  and  of  the  impulses  transmitted  to  this  organ  by  the  extrinsic 
nerves.  We  must  then  seek  the  position  of  the  center  which  perceives 
the  sensation  of  hunger. 

It  will  be  simplest  to  consider  first  the  effect  of  section  of  the  extrinsic 
nerves  in  observations  made  on  lower  animals.  Section  of  the  splanchnic 
nerves  increases  gastric  tonus  and  augments  the  gastric  hunger  contrac- 
tions. Section  of  both  vagus  nerves,  performed  of  course  below  the  level 
of  the  heart,  leaves  the  stomach  in  a  more  or  less  hypotonic  condition. 
The  tonus  is  not  entirely  abolished;  it  varies  somewhat  from  day  to  day, 
and  may  become  quite  pronounced  even  though  the  vagi  are  cut.  In 
this  hypotonic  state  the  hunger  contractions  are  diminished  in  rate 
and  regularity.  Section  of  both  the  splanchnic  and  vagus  nerves  throws 
the  stomach  into  a  permanent  hypotonus,  except  in  prolonged  starva- 
tion, when  hunger  contractions  develop  that  are  usually  of  great  ampli- 
tude and  with  particularly  long  intervals  between  the  contractions. 
The  general  conclusion  to  be  drawn  from  these  experiments  is  that, 
although  completely  isolated  from  the  central  nervous  system,  the 
stomach  still  exhibits  typical  hunger  contractions,  which  must  therefore 
be  essentially  dependent  upon  an  automatic  mechanism  in  the  stomach 
wall  itself.  Over  this  mechanism,  extrinsic  nerve  impulses  have  merely  a 
regulatory  control. 

Variations  and  Inhibitions  of  the  Hunger  Contractions 

The  afferent  stimuli  that  may  set  up  impulses  traveling  by  the  extrin- 
sic nerves  to  the  stomach  are  conveyed  by  the  nerves  of  sense  or  are  of 
psychic  origin.  Stimulation  of  the  gustatory  end  organs  in  the  mouth, 
as  by  chewing  palatable  food,  always  causes  an  inhibition  of  the  tonus 
and  a  diminution  or  disappearance  of  the  hunger  contractions.  Even  the 
chewing  of  indifferent  substances,  such  as  paraffin,  suffices  to  produce 
distinct  inhibition,  unless  in  a  case  in  which  the  contraction  has  passed 
into  a  tetanus.  It  is  of  interest  that  SAvallowing  movements,  in  the  ab- 
sence of  any  food  substance  in  the  mouth,  are  sufficient  to  produce  a 
transitory  inhibition  of  the  gastric  tonus — a  receptive  relaxation  of  the 


478  DIGESTION 

stomach,  as  it  has  been  aptly  called.  The  diminution  in  tonus  and 
hunger  contractions  in  these  various  ways  is  accompanied  b\r  a  diminu- 
tion in  the  hunger  pains. 

Afferent  nerve  stimulation  affecting  the  hunger  contractions  may  also 
originate  in  the  stomach  mucosa  itself,  as  has  been  shown  by  Carlson  on 
his  patient  by  introducing  the  various  substances  to  be  tested  through 
a  tube  into  the  stomach.  A  glassful  of  cold  water  introduced  in  this 
May  inhibits  the  tonus  and  the  hunger  contractions  for  from  three  to  five 
minutes  unless  these  are  severe,  this  inhibition  being  followed  by  no 
augmentation  either  of  the  tonus  or  of  contractions.  Ice-cold  water  has 
a  greater  effect  than  water  at  body  temperature.  This  result  is  some- 
what different  from  that  which  most  men  experience  as  the  result  of 
drinking  a  glass  of  cold  water. 

Weak  acids  of  strengths  varying  up  to  that  found  present  in  the 
gastric  juice  itself — 0.5  per  cent — cause  a  marked  inhibition  of  the 
hunger  movements,  but  this  inhibition  does  not  persist  until  all  the  acid 
has  escaped  from  the  stomach  or  been  neutralized,  which  explains  why 
hunger  contractions  should  still  occur  when  an  acid  secretion  is  present 
in  the  stomach,  as  in  starvation.  Normal  gastric  juice  itself  produces 
an  inhibition,  which  is  no  doubt  dependent  upon  the  acid  which  it  con- 
tains, and  it  is  probable  that,  at  the  same  time  that  it  leads  to  inhibition 
of  the  hunger  contractions,  the  acid  initiates  peristalsis  of  the  pyloric 
region  (see  page  453).  Weak  alkaline  solutions  have  no  greater  effect  on 
the  hunger  contractions  than  an  equal  volume  of  water.  Weak  solu- 
tions of  local  anesthetics,  such  as  phenol  or  chloretone,  are  without  effect. 

With  regard  to  alcoholic  beverages  interesting  results  were  obtained. 
Wine,  beer,  brandy,  and  diluted  pure  alcohol  inhibit  both  the  tonus  and 
the  contractions.  The  duration  of  this  inhibition  varies  directly  with  the 
quantity  of  the  beverage  introduced  into  the  stomach  and  with  its  alco- 
hol percentage.  These  observations  are  apparently  not  in  harmony  with 
the  experience  of  most  men  that  the  taking  of  alcoholic  beverages  serves 
to  awaken  or  increase  the  appetite,  the  difference  being  no  doubt  due  to 
the  fact  that  appetite  and  hunger  contractions  of  the  stomach  are  not 
dependent  on  each  other,  appetite  being,  as  we  have  seen,  a  complex 
psychic  affair,  whereas  the  hunger  contractions  depend  upon  a  local 
mechanism  in  the  stomach  wall  itself. 

As  the  inhibition  produced  in  one  or  other  of  these  ways  passes  off, 
the  hunger  contractions  are  resumed  at  their  previous  intensity  and  not 
in  an  augmented  form.  From  the  promptness  of  the  inhibition,  it  would 
appear  that  the  stomach  contractions  are  affected,  not  reflexly  through 
the  central  nervous  system  or  by  changes  in  the  chemical  composition 
of  the  blood,  but  by  a  direct  action  on  the  neuromuscular  mechanism 


HUNGEB    AM)    APPETITE  479 

iii  the  stomach  walls,  and  it  is  important  to  bear  iii  mind  thai  the 
inhibitory  effects  on  the  stomach  contractions  of  the  fundus  may  proceed 
quite  independently  of  the  changes  in  the  pyloric  region  that  are  con- 
cerned with  the  mechanical  processes  of  digestion.  After  one  or  both 
of  the  extrinsic  nerves  of  the  stomach  were  severed  in  dogs,  a  certain 
degree  of  inhibition  could  still  he  induced  by  the  above  methods,  indicat- 
ing that,  although  section  of  the  extrinsic  nerves  depresses  the  inhibitory 
reflex,  it  does  not  abolish  it, 

Various  mitigations  of  the  hunger  contractions  have  been  discovered. 
Smoking  has  this  effect,  and  compression  of  the  abdomen  by  tightening 
the  belt  also  inhibits  the  contractions  provided  they  are  not  of  marked 
intensity.  Considerable  muscular  exercise,  such  as  brisk  walking  or 
running,  causes  inhibition,  which  usually  persists  until  after  the  exer- 
cise is  discontinued.  When  the  tonus  and  contractions  return,  in  this 
case,  they  seem  to  be  somewhat  more  pronounced.  Application  of  cold 
to  the  surface  of  the  body — as  by  placing  an  ice  pack  on  the  abdomen 
or  taking  a  cold  douche,  procedures  which  are  well-known  to  induce 
increased  neuromuscular  tonus,  in  general — causes  an  inhibition  of  the 
gastric  tonus  and  hunger  contractions,  the  degree  of  which  is  roughly 
proportional  to  the  intensity  of  the  stimulation.  There  is  certainly  never 
an  increase  in  the  gastric  tonus  or  hunger  contractions.  If  such  stimula- 
tion is  maintained,  the  inhibitory  effects  on  the  stomach  gradually 
diminish,  even  though  the  individual  be  shivering  intensely. 

With  regard  to  the  nerve  centers  concerned  in  these  phenomena,  little 
that  is  definite  is  known.  The  sensory  nuclei  of  the  vagus  nerve  in  the 
medulla  must  be  considered  as  the  primary  hunger  center,  and  through 
this  center,  not  only  influences  affecting  the  stomach  contractions,  but 
also  those  associated  with  the  hunger  sensations,  must  be  mediated.  It 
would  appear  from  observations  on  the  hunger  behavior  .of  decerebrate 
animals  that  there  can  be  no  hunger  center  located  on  the  cerebral  cortex 
itself,  for  such  animals  exhibit  practically  the  same  hunger  effects  as 
normal  animals.  It  is  interesting  to  note  that,  at  least  in  the  case  of 
decerebrate  pigeons,  this  hunger  behavior  entirely  disappears  on  removal 
of  the  optic  thalami,  where  important  nerve  centers  having  to  do  with 
the  bodily  responses  of  the  animal  to  hunger  impulses  would  therefore 
appear  to  be  located.  These  observations  support  the  suggestion  that 
has  been  made  by  several  neurologists  that  the  sense  of  pain  is  located 
somewhere  in  the  thalamic  region. 

Concerning  the  influence  of  psychic  states,  Carlson  says  that  in  his 
own  case  the  hunger  contractions  became  weaker  and  the  intervals 
between  them  greater  when  he  was  suddenly  awakened  during  his 
fast  and  saw  two  of  his  friends  partaking  at  his  bedside  of  a  "feast  of 


480  DIGESTION 

porterhouse  steak  with  onions,  potatoes,  and  a  tomato  salad."  These 
results  are  no  doubt  due  to  local  inhibition  dependent  upon  the  psychic 
secretion  of  appetite  gastric  juice.  When  no  such  juice  is  produced, 
the  sight  and  smell  of  good  food  does  not  appear  to  affect  materially 
the  hunger  contractions  of  the  stomach.  No  doubt  it  stimulates  the 
appetite,  but  that,  as  we  have  seen,  is  a  psychic  affair. 


CHAPTER  LV 

THE  BIOCHEMICAL  PROCESSES  OF  DIGESTION 

In  a  book  designed  primarily  for  clinical  workers,  it  would  be  out  of 
place  to  enter  into  details  concerning  the  biochemical  processes  taking 
place  during  the  digestive  process.  There  is,  however,  a  certain  amount 
of  fundamental  knowledge  which  it  is  essential  that  we  should  consider. 
In  the  first  place  it  should  be  borne  in  mind  tha,t  in  the  digestion  of 
carbohydrates  and  proteins,  various  intermediate  stages  are  passed 
through  before  the  final  absorption  "products  are  formed.  The  highly 
complex  molecule  of  which  protein,  for  example,  is  composed,  is  first 
of  all  broken  down  into  several  smaller  but  still  highly  complex  mole- 
cules, each  of  which  then  undergoes  further  disruption,  until  ultimately 
the  amino  acids  are  set  free.  Certain  enzymes,  such  as  trypsin,  can 
carry  this  process  from  the  beginning  through  the  greater  part  of  its 
course  without  the  assistance  of  other  enzymes,  but  in  the  natural  proc- 
ess of  digestion,  as  it  occurs  in  the  gastrointestinal  tract,  the  different 
stages  of  the  disruption  are  controlled  by  different  enzymes.  One  enzyme 
prepares  the  food  for  action  by  the  next.  This  interdependence  of  the 
actions  of  the  enzymes  demands  that  some  provision  should  be  made 
whereby  each  enzyme  is  secreted  at  the  proper  time;  that  is,  when  the 
foodstuff  has  already  been  prepared  for  its  action  by  that  of  its  prede- 
cessor. Thus,  it  would  be  useless  after  food  is  taken  for  the  gastric  and 
pancreatic  juices  to  be  secreted  at  the  same  time.  Instead,  the  gastric 
juice  is  secreted  first,  and  the  pancreatic  only  after  the  food  has  been 
prepared  for  its  action.  This  correlation  in  function  we  have  already 
seen  to  be  dependent  largely  on  the  action  of  hormones. 

DIGESTION  IN  THE  STOMACH 

The  gastric  juice  contains  two  important  digestive  agencies.:  (1)  the 
enzyme,  pepsin,  and  (2)  hydrochloric  acid.  It  is  particularly  in  juices 
secreted  in  the  cardiac  end  of  the  stomach  that  these  two  substances  are 
found  present;  towards  the  pyloric  end  the  hydrochloric  acid  entirely 
disappears,  and  the  pepsin  content  becomes  distinctly  less. 

481 


482  DIGESTION 

The  Functions  of  Hydrochloric  Acid 

The  functions  of  hydrochloric  acid  may  he  conveniently  divided  into 
physiological  and  biochemical.  The  former  functions  have  to  do  with 
the  control  of  the  movements  of  the  stomach,  including  the  opening 
of  the  pyloric  sphincter,  and,  after  the  chyme  has  entered  the  duodenum, 
■with  the  secretion  of  pancreatic  juice  and  bile.  The  biochemical  functions 
are  concerned:  (1)  in  assisting  the  pepsin  in  the  digestion  of  proteins, 
(2)  in  bringing  about  a  certain  amount  of  inversion  of  disaccharides, 
and  (3)  in  having  an  antiseptic  action  on  the  stomach  contents.  Re- 
garding the  last  mentioned  of  these  functions,  it  may  be  said  that  the 
chyme,  as  it  is  ejected  from  the  stomach,  is  usually  sterile,  although  it 
may  contain  spores  and  certain  bacteria  that  are  protected  against  the 
digestive  agencies  of  the  stomach.  This  protection  is  afforded  by  an 
outer  covering  of  a  chitinous  nature  ( spores),  or,  as  in  the  case  of  the 
tubercle  bacillus,  by  a  covering  of  waxlike  material.  It  is  believed  that 
persons  with  strictly  normal  digestion  are  much  less  liable  to  infection 
by  such  bacteria,  as  those  of  typhoid  and  cholera,  than  persons  with  less 
active  gastric  secretion.  When  the  acid  of  the  gastric  juice  falls  below 
the  level  at  which  it  develops  an  antiseptic  action,  various  bacteria  and 
yeasts  grow  in  the  stomach  contents,  producing  by  the  resulting  fermen- 
tation irritating  organic  acids  and  gases.  It  is  under  these  conditions 
that  yeasts,  sarcina?,  and  lactic  and  butyric  acid  bacilli  find  in  the  gastric 
contents  a  suitable  nidus  on  which  to  grow. 

The  Amount  of  Acid 

It  has  long  been  known  that  considerable  variations  in  the  amount  of 
hydrochloric  acid  in  the  gastric  juice  are  associated  with  symptoms  of 
indigestion.  On  this  account  a  more  or  less  elaborate  technic  has  been 
developed  for  the  purpose  of  determining  the  amount  of  hydrochloric 
acid  in  the  gastric  contents.*  There  are  three  things  in  connection  with 
this  activity  that  we  may  measure:  (1)  the  total  titrable  hydrochloric 
acid;  (2)  the  free  hydrochloric  acid;  and  (3)  the  actual  hydrogen-ion 
concentration.  The  determination  of  the  total  available  acids  is  made 
by  titrating  a  measured  quantity  of  gastric  juice  against  a  standard 
alkali,  using  phenolphthalein  as  an  indicator.  By  this  method  about 
75  c.c.  of  decinormal  alkali  solution  are  required  to  neutralize  100  c.c. 
of  normal  gastric  juice.  The  determination  of  the  free  hydrochloric  acid 
is  made  by  using  special  indicators,  such  as  those  of  Giinzberg  and 
Topfer,  which  change  color  at  a  hydrogen-ion  concentration  of  about 
10~s  (see  page  27).     To  produce  this  hydrogen-ion  concentration,  a  con- 


"The  methods  can  be  found  in  any  volume  on  clinical  diagnosis. 


THE    BIOCHEMICAL    PROCESSES   OF   DIGESTION  483 

siderable  quantity-  0.05  per  eenl  or  more — of  an  organic  acid  is  neces- 
sary, whereas  it  requires  only  a  trace  of  hydrochloric  acid.  Normal 
human  gastric  juice,  when  titrated  with  one  of  these  indicators,  gives 
a  figure  which  corresponds  to  about  0.0:$  X  hydrochloric  acid  (see  page 
22).  For  the  accurate  determination  of  the  hydrogen-ion  concentration, 
il  is  necessary  to  use  the  gas-chain  method   (see  page  29). 

When  gastric  juice  is  collected  through  a  fistula  from  an  empty 
stomach,  very  little  difference  will  be  found  between  the  free  hydro- 
chloric acid  and  the  total  acid;  that  is,  between  the  results  obtained  by 
the  second  and  the  first  of  the  methods  described  above.  This  is  because 
in  such  juice  there  is  no  organic  matter  capable  of  combining  with  the 
hydrochloric  acid,  and  there  are  no  other  acids,  such  as  lactic  or  butyric, 
which  might  be  produced  by  fermentative  processes.  The  difference 
between  the  two  titrations,  however,  becomes  quite  marked  when  pro- 
tein food  is  undergoing  digestion  in  the  stomach,  because  at  its  different 
stages  of  digestion  protein  combines  with  increasing  quantities  of  the 
hydrochloric  acid.  The  pathologic  condition  in  which  there  is  most 
definitely  a  diminution  of  the  hydrochloric  acid  is  cancer,  either  of  the 
stomach  itself  or  occasionally  of  some  other  part  of  the  body.  An  in- 
crease is  particularly  marked  in  ulcer  of  the  stomach.  A  considerable 
variation  in  hydrochloric  acid  may  however  be  the  result  merely  of  func- 
tional  (neurotic)   conditions. 

The  Sofrce  op  the  Acid 

A  question  that  has  puzzled  physiologists  for  many  years  concerns  the 
mechanism  by  which  hydrochloric  acid  is  secreted.  The  percentage  of 
hydrochloric  acid  in  the  gastric  juice  is  considerably  above  that  at  which 
any  animal  cells  can  live,  and  yet  this  acid  is  secreted  by  the  lining 
membrane  of  the  stomach,  its  source  being,  of  course,  the  sodium 
chloride  of  the  blood  plasma.  How  then  do  the  cells  of  the  gastric 
glands  bring  about  the  separation  of  this  powerful  acid  from  the  per- 
fectly neutral  blood  plasma?  In  the  first  place,  it  is  significant  that  the 
mucous  membrane  of  the  stomach  contains  a  higher  percentage  of 
chlorine  than  the  average  of  other  organs  and  tissues,  indicating  that  it 
has  the  power  of  abstracting  chlorine  from  the  blood.  The  excess  of 
chlorine  in  the  mucosa  must,  moreover,  be  but  a  very  small  fraction  of 
that  actually  secreted  into  the  the  gastric  juice.  The  chlorine  content 
of  the  mucosa  of  the  cardiac  end  is  considerably  greater  than  that  of  the 
pyloric.  These  facts  indicate  that  chlorine  is  attracted  by  the  gastric 
cells,  but  they  throAv  no  light  on  the  question  as  to  where  the  hydro- 
chloric acid  is  really  formed.  Is  it  in  the  cells,  or  only  in  the  lumen  of 
the  gland  tubes?    That  is  to  say,  is  it  formed  before  or  after  the  gastric 


484  DIGESTION 

juice  has  been  secreted  from  the  cells?  After  intravenous  injection  of 
solutions  of  potassium  ferrocyanide  and  some  inert  salt  of  iron,  such  as 
one  of  the  scale  preparations,  examination  of  the  gastric  glands  has 
shown  that  the  prussian  blue  reaction,  which  requires  the  presence  of 
free  mineral  acid,  is  most  pronounced  in  certain  of  the  parietal  cells.  A 
considerable  amount  of  the  precipitate  is,  however,  also  visible  in  the 
lumen  of  the  glands  and  in  the  stomach  itself.  Certain  observers  affirm 
that,  although  some  of  the  parietal  cells  may  take  the  stain,  the  vast 
majority  of  them  do  not  do  so;  and,  moreover,  that  cells  incapable  of 
forming  hydrochloric  acid  (e.  g.,  of  the  liver)  may  also  become  stained, 
and  that  the  precipitation  may  occur  in  the  blood  and  lymph. 

The  confusion  in  the  results  by  these  methods  prompted  A.  B.  Macal- 
lum14  and  Miss  M.  P.  Fitzgerald  to  investigate  the  distribution  of  the 
chlorine  in  the  cells  by  a  microchemical  method,  in  which  the  chlorides 
were  precipitated  with  silver  nitrate  and  the  silver  chloride  then  reduced 
by  exposing  the  section  to  light.  It  was  found  that  both  kinds  of  gas- 
tric-gland cell,  chief  and  parietal,  but  particularly  the  parietal,  gave  the 
chloride  reaction.  Using  as  a  stain  a  substance  (cyaninine)  which  reacts 
blue  with  acid  and  red  with  alkali,  Harvey  and  Bensley,15  however,  aver 
that  the  secretion  of  the  glands  is  practically  neutral  until  the  foveola  is 
reached,  where  the  stain  becomes  blue,  indicating  an  acid  reaction. 
This  seems  to  show  that  the  acid  is  not  really  secreted  by  the  cells  of 
the  gastric  gland,  but  is  formed  after  secretion. 

According  to  the  latter  investigators,  the  chlorine  is  secreted  by  the 
cells  into  the  fovea  as  some  weak  chloride,  such  as  ammonium  chloride, 
or  it  may  be  as  an  ester.  Shortly  after  its  secretion  this  weak  chloride 
undergoes  a  hydrolytic  or  other  dissociation,  during  which  free  hydro- 
chloric acid  is  liberated  and  ammonia  or  some  other  weak  base  set  free. 
Of  these  two  products  of  the  reaction  the  weak  base  is  reabsorbed  by 
the  gland  cells,  but  the  hydrochloric  acid  is  left  behind  because  the 
cells  are  impervious  to  it.  Indirect  evidence  in  support  of  this  view  is 
afforded  by  certain  other  instances  in  which  hydrochloric  acid  is  pro- 
duced by  the  action  of  cells ;  thus,  the  mold  Penicillium  glaucum  when  it 
is  grown  in  a  medium  containing  ammonium  chloride  absorbs  the  am- 
monia but  leaves  the  hydrochloric  acid.  The  high  penetrating  power 
of  the  ammonia  ion  in  practically  all  cells,  and  the  fact  that  the  mucosa 
of  the  stomach  contains  a  higher  percentage  of  ammonia  than  any  other 
tissue  in  the  body,  must  also  be  considered  as  circumstantial  evidence 
in  favor  of  this  view. 

Whatever  be  the  mechanism  by  which  hydrochloric  acid  is  produced, 
there  is  no  doubt  that  the1  epithelium  is  impenetrable  to  it.  When  the 
vitality  of  the  epithelium  becomes  lowered,  as  in  anemia  or  after  partial 


THE    BIOCHEMICAL   PROCESSES   OF   DIGESTION  485 

occlusion  of  the  arteries,  the  acid  may  penetrate  the  cells  and  cause 
digestion  of  the  stomach  walls.  Hyperacidity  may  on  this  account 
become  dangerous,  as  it  lowers  the  resistance  of  the  cell. 

The  digestive  action  of  hydrochloric  acid  is  closely  linked  with  that  of 
pepsin,  with  which  it  will,  therefore,  be  considered. 

The  Action  of  Pepsin 

It  is  commonly  believed  that  before  its  secretion  pepsin  exists  in  the 
cells  of  the  gastric  glands  as  zymogen  granules.  The  chief  evidence  for 
this  belief  appears  to  be  that  after  considerable  activity  the  amount  of 
zymogen  granules  in  the  gland  cells  is  found  to  be  decidedly  dimin- 
ished. By  such  an  hypothesis  it  is  easy  to  explain  certain  interesting 
results  concerning  the  effect  of  weak  alkali  on  the  activities  of  extracts 
of  the  mucous  membrane  of  the  stomach.  When  the  mucous  membrane 
is  extracted  with  weak  acids,  the  extract  is  very  active  proteolytically. 
If  this  so-called  pepsin  solution  be  made  faintly  alkaline,  or  even  only 
neutralized,  and  again  made  acid,  it  will  be  found  to  have  lost  much, 
if  not  all,  of  its  activity.  On  the  other  hand,  an  aqueous  extract  may  be 
rendered  slightly  alkaline  for  a  short  time  and  still  display  its  digestive 
activity  on  subsequent  acidification.  The  extract  made  with  water  is 
therefore  much  more  resistant  toward  alkali  than  that  made  with  weak 
acid,  and  the  difference  is  explained  on  the  supposition  that  the  watery 
extract  contains  pepsinogen,  whereas  the  acid  extract  contains  pepsin. 

It  is  believed  that  there  are  several  varieties  of  pepsin,  because  the 
optimum  concentration  of  acid  in  which  pepsin  derived  from  the  stomachs 
of  different  animals  acts  is  not  always  the  same.  Pepsin  of  the  dog,  for 
example,  acts  best  in  a  hydrogen-ion  concentration  corresponding  to 
that  of  a  0.05  N.  hydrochloric  acid  solution,  whereas  that  of  the  human 
stomach  works  best  at  a  concentration  of  0.03  N.  Different  pepsin 
solutions  also  show  a  difference  with  regard  to  the  optimum  tempera- 
ture at  which  they  act,  and  with  regard  to  the  nature  of  the  protein 
which  they  most  readily  attack.  Thus,  the  pepsin  of  a  calf's  stomach 
digests  casein  very  rapidly,  but  coagulated  egg  white  only  slowly, 
whereas  the  pepsin  of  the  pig's  stomach  acts  on  both  these  proteins  at 
about  the  same  rate. 

It  is  well  known  that  the  activity  of  pepsin  can  proceed  only  in  the 
presence  of  acids,  but  this  action  of  acids  does  not  appear  to  depend  on 
the  hydrogen-ion  concentration  alone,  for  when  equal  quantities  of  the 
same  pepsin  are  mixed  with  quantities  of  different  acids  so  that  the 
hydrogen-ion  concentration  of  the  mixtures  is  uniform,  it  is  found  that 
digestion  proceeds  most  rapidly  with  hydrochloric  acid  and  least  rapidly 
with  sulphuric  acid.     The  S04  ion  seems,  therefore,  to  be  unfavorable 


486  DIGESTION 

for  peptic  activities.  The  acid  seems  to  combine  with  the  protein  before 
the  pepsin  attacks  the  latter;  for,  if  we  first  combine  the  protein  with 
acid  and  then  Avash  away  all  traces  of  free  acid,  the  protein  can  be 
digested  in  a  neutral  pepsin  solution  without  the  liberation  of  any  free 
acid. 

There  is  evidence  to  show  that  pepsin  itself  also  becomes  combined 
with  the  protein  during  the  digestive  process.  If  a  piece  of  protein  such 
as  fibrin  be  immersed  in  a  solution  of  pepsin  and  then  taken  out  and 
washed  thoroughly  to  set  rid  of  all  adherent  pepsin,  it  Avill  be  found,  on 
placing  it  in  a  hydrochloric  acid  solution  of  the  proper  strength,  that 
peptic  digestion  proceeds.  Advantage  may  be  taken  of  this  fact  to 
separate  pepsin  from  a  solution,  but  the  best  protein  to  use  for  this  pur- 
pose is  not  fibrin  but  elastin.  By  such  a  method  it  has.  for  example, 
been  shown  that  there  is  some  pepsin  in  the  intestinal  contents,  proving 
thus  that  when  the  chyme  passes  into  the  intestine,  the  pepsin  is  not,  as 
used  to  be  thought,  immediately  killed  by  the  proteolytic  enzyme. 

Products  of  Peptic  Digestion 

With  regard  to  the  products  of  gastric  digestion,  little  can  be  said 
here.  The  first  product  is  a  metaprotein  known  as  -acid  albumin  or 
syntonin.  It  is  precipitated  from  the  digestion  mixture  by  neutraliza- 
tion. The  next  product  is  known  as  primary  proteose,  being  precipi- 
tated by  half  saturation  with  ammonium  sulphate.  The  third  product 
is  secondary  proteose,  produced  by  complete  saturation  with  the  above 
reagent ;  and  after  all  these  bodies  have  been  separated  out,  there  re- 
mains in  solution  the  fourth  product — peptone — which  among  other 
things  is  characterized  by  the  fact  that  with  the  biuret  test  it  gives  not 
a  violet  but  a  rose-pink  color. 

It  has  often  been  claimed  that  along  with  these  products  a  certain 
amount  of  free  amino  acids  may  also  appear  in  a  peptic  digestive  mix- 
ture. This,  however,  may  be  due  to  the  action  of  erepsin,  which  is 
usually  present  in  pepsin  preparations.  It  is  important  to  note  that  the 
term  proteose  is  a  general  one,  and  that  there  ai-e  probably  many  varieties 
of  this  substance,  differing  from  one  another  according  to  the  protein 
from  which  they  are  derived. 

The  change  produced  by  pepsin  and  hydrochloric  acid  is  of  the  nature 
of  an  hydrolysis,  for  it  has  been  found  that  the  amount  of  hydrogen  and 
oxygen  in  the  digestive  products  is  greater  than  that  in  the  original 
protein.  It  is  by  a  similar  process  of  hydrolysis  that  the  other  proteolytic 
enzymes,  such  as  pancreatin  and  erepsin,  operate,  but  this  does  not 
imply  that  the  exact  grouping  that  is  split  apart  by  the  hydrolytic  proc- 


THE   BIOCHEMICAL    PROCESSES   OF    DIGESTION  487 

ess  is  the  same  for  each  of  these  enzymes.  Indeed,  there  is  considerable 
evidence  that  pepsin  does  not,  like  the  other  enzymes,  break  np  the  long 
chain  of  amino  acids  that  are  linked  together  to  compose  the  polypep- 
tides, but  that  it  only  splits  the  big  molecule  of  albumin  or  globulin 
into  several  large  groups,  each  of  which  is  composed  of  long  amino-acid 
chains.  Its  action  appears  to  be  analogous  with  that  of  amylase  on 
starch,  by  which,  it  will  be  remembered,  the  big  polysaccharide  mole- 
cule is  split  into  smaller  polysaccharide  molecules,  which  then  become 
attacked  by  the  dextrinase  and  split  into  disaccharide  molecules  (see 
page  656).  The  evidence  in  support  of  this  view  is:  (1)  that  pepsin  is 
unable  to  digest  polypeptides,  and  (2)  that  it  is  able  to  digest  certain 
proteins  upon  -which  erepsin  (see  page  400)  has  no  action. 

The  hydrolytic  splitting  of  large  into  smaller  protein  molecules,  like 
that  by  which  the  chains  of  amino  acids  in  the  polypeptides  are  subse- 
quently broken  up,  consists  in  a  breaking  of  amino-carboxyl  linkings 
(NHCO)  (see  page  598),  with  the  consequent  liberation  of  a  large  num- 
ber of  unattached  amino  groups.  The  number  of  these  free  amino  groups 
can  be  determined  quantitatively  by  the  formaldehyde  titration  method 
of  Sorensen.*  By  this  method  it  can  be  shown  that  from  the  very  start 
of  peptic  digestion  the  number  of  free  amino  groups  increases,  and  pari 
passu  the  power  of  the  digestive  products  to  combine  with  free  hydro- 
chloric acid.  Indeed,  when  the  experiments  are  done  quantitatively  and 
the  digestion  allowed  to  proceed  for  a  considerable  time,  the  increase  in 
the  formol  titration  is  practically  equal  to  the  decrease  in  the  free  acids 
as  determined  by  the  Giinsberg  reagent. 

The  rate  of  peptic  digestion  is  usually  estimated  by  the  law  of  Schiitz 
and  Borissow,  according  to  Avhich  the  amount  of  coagulated  albumin 
that  is  digested  in  a  Mett's  tube  is  proportional  to  the  square  root  of  the 
amount  of  pepsin. f 

The  pepsin  which  leaves  the  stomach  in  the  chyme  is  not  all  destroyed 
in  the  intestine,  as  was  at  one  time  believed  to  be  the  case,  for,  as  we 
have  seen  above,  some  pepsin  can  be  detected  in  the  gastrointestinal  con- 
tents. A  part  of  the  pepsin  may  be  absorbed  into  the  blood  and  carried 
back  to  the  gastric  glands  to  be  used  again.  This  would  account  for  the 
presence  of  antipepsin  in  the  blood,  and  also  for  the  presence  of  pepsin 
in  the  urine.  It  is  probable,  however,  that  most  of  the  pepsin  is  de- 
stro}-ed  after  it  enters  the  intestine. 


*In  this  method  the  basic  character  of  the  amino  acids  is  destroyed  by  the  formaldehyde,  so 
that  a  higher  degree  of  acidity  develops  in  the  mixture.  By  determining  the  increased  acidity  by 
titration   with  alkali,   an   estimate   is  obtained    of   the   number   of  amino   groups.      (See   page    599.) 

fThe  amount  of  coagulated  egg  albumin  digested  is  ascertained  by  measuring  the  length  digested 
away  from  the  end  of  a  column  of  coagulated  egg  white  contained  in  a  glass  tube  (Mett's  method). 
(Sec  Cobb,  P.  W.:     Am.  Jour.   Physiol.,   1905,  xiii,  448.) 


488  DIGESTION 

Clotting-  of  Milk  in  the  Stomach 

Besides  its  power  of  digesting  protein,  the  gastric  juice  is  also  endowed 
with  the  property  of  clotting  milk.  This  action  is  commonly  attributed 
to  the  presence  of  another  enzyme  besides  pepsin,  namely,  rennin;  but 
in  recent  years  considerable  controversy  has  raged  around  the  question 
as  to  whether  pepsin  and  rennin  are  not  the  same  thing.  One  strong 
argument  in  favor  of  this  view  is  that  all  digestive  juices  that  are  capable 
of  digesting  protein  can  also  clot  milk.  In  any  case,  when  gastric  juice 
acts  on  milk,  it  splits  the  casein*  of  the  milk  into  two  portions,  one  of 
which,  called  paracasein,  immediately  combines  with  calcium  to  form  an 
insoluble  colloidal  compound,  which  is  precipitated  and,  by  entangling 
the  fat  of  the  milk,  forms  the  clot;  the  other  protein  remains  in  solution 
and  is  known  as  whey  albumose.  From  studies  on  molecular  weight  it 
is  believed  that  the  paracasein  is  produced  from  casein  by  the  splitting 
of  the  molecule  of  the  latter  into  two,  from  Avhich  it  would  appear  that 
the  action  of  this  enzyme  is  nothing  more  than  the  first  stage  in  the 
hydrolysis  of  the  casein  molecule.  The  whey  albumose,  according  to  this 
view,  is  a  by-product. 

There  are  many  investigators,  however,  who  believe  that  rennin  and 
pepsin  are  not  identical,  since  an  infusion  of  the  stomach  of  a  calf  has  a 
powerful  clotting  action  on  milk  but  a  very  weak  digestive  one  on  egg 
white,  whereas  a  similar  infusion  from  the  stomach  of  a  pig  shows  exactly 
the  reverse  properties.  This  question  is  one  of  so  controversial  a  na- 
ture that  it  would  be  out  of  place  to  go  into  it  further  here.  It 
should  be  pointed  out,  however,  that,  when  the  gastric  contents  are  acid 
in  reaction,  milk  will  become  clotted  by  the  action  of  the  acid  itself 
quite  independently  of  any  pepsin  or  rennin  the  juice  may  contain. 
This  acid  clotting  of  milk  is  probably  of  a  different  chemical  nature 
from  that  produced  by  the  enzymes. 

On  other  foodstuffs  than  proteins  the  action  of  the  gastric  juice  is 
relatively  unimportant,  although  polysaccharides  may  be  considerably 
broken  down  in  the  cardiac  end  of  the  stomach  on  account  of  the  action 
of  swallowed  saliva  (see  page  454),  and  disaccharides,  as  we  have  seen, 
may  become  split  by  the  hydrolyzing  effect  of  the  hydrogen  ion.  Fat 
digestion  also  takes  place  in  the  stomach  when  the  fat  is  taken  in  an 
emulsified  condition,  as  in  milk  and  egs  yolk,  but  not  when  in  masses, 
as  in  meat  or  butter.  This  action  is  due  to  the  presence  of  a  fat-splitting 
enzyme,  or  lipase,  in  the  gastric  juice. 


*In  the  above  nomenclature  casein  is  the  same  as  caseinogen,   and  paracasein  the  same  as  casein, 
of  the  English  physiologists. 


CHAPTER  LVI 
THE  BIOCHEMICAL  PROCESSES  OF  DIGESTION  (Cont'd) 

DIGESTION  IN  THE  INTESTINES 

The  further  changes  which  the  half-digested  foodstuffs  in  the  chyme 
undergo  in  the  intestinal  canal  depend  on  the  enzymes  present  in  the 
secretion  of  the  various  glands  and  on  the  presence  of  bacteria.  The 
most  important  of  the  digestive  juices  are  the  pancreatic  juice  and  bile. 
The  latter,  however,  does  not  contain  any  enzyme,  its  influence  on  diges- 
tion being  entirely  adjuvant. 

Pancreatic  Digestion 

When  we  were  considering  the  mechanism  of  secretion  of  the  pan- 
creatic juice,  we  saw  that  the  juice  produced  by  the  action  of  secretin  on 
the  gland  cells  does  not  contain  any  active  proteolytic  enzyme,  although 
it  contains  one  capable  of  acting  on  polysaccharides  and  another,  on  fat. 

The  Action  of  Trypsin 

When  this  juice  is  mixed  with  the  secretion  of  the  duodenum  or  of 
the  upper  part  of  the  small  intestine,  it  immediately  develops  powerful 
proteolytic  power.  The  same  result  may  also  be  obtained  by  mixing  it 
with  an  extract  of  the  mucous  membrane  of  the  duodenum  made  with 
dilute  bicarbonate  solution.  A  very  small  amount  of  the  extract  is 
capable  of  increasing  the  digestive  activity  of  a  very  considerable  quan- 
tity of  pancreatic  juice,  showing  that  the  action  depends  on  the  presence 
of  an  enzyme  which  has  been  called  enterokinase.  This  influence  of  the 
intestinal  secretion  is  readily  destroyed  by  heating. 

Large  quantities  of  alkali  are  contained  in  the  pancreatic  juice  and 
bile,  so  that  in  the  upper  reaches  of  the  intestine  the  acidity  of  the 
chyme  is  practically  neutralized.  A  little  lower  down,  however,  an  acid 
reaction  may  again  develop  (see  page  505).  On  account  of  these  facts  it 
has  been  concluded  that  the  activity  of  trypsin  is  most  rapid  in  the  pres- 
ence of  a  slight  excess  of  hydroxyl  ions;  i.  e.,  in  a  weakly  alkaline  solu- 
tion. It  is  interesting  to  note  that,  as  a  result  of  the  great  secretion  of 
alkali  by  the  pancreas,  extracts  of  this  organ  after  death  show  a  very 
high  degree  of  acidity  in  comparison  with  extracts  from  other  organs 

439 


490  DIGESTION 

and  tissues.  It  has  also  recently  been  shown  that  the  activity  of  trypsin 
does  not  depend  on  the  presence  of  free  hydroxyl  ions,  but  that  it  may 
proceed  in  the  presence  of  free  acid,  even  up  to  a  strength  of  CH  =  1.5. 
If  pepsin  is  present  together  with  trypsin  in  a  distinctly  acid  solution, 
the  pepsin  seems  to  destroy  the  trypsin,  unless  the  mixture  contains  a 
considerable  quantity  of  protein,  when  the  tryptic  activity  may  persist 
even  for  several  hours.  A  practical  conclusion  that  Ave  may  draw  from 
these  results  is  to  the  effect  that  preparations  of  trypsin — the  so-called 
pancreatin,  for  example — if  given  with  the  food,  may  pass  in  an  active 
condition  into  the  duodenum,  where,  in  the  more  favorable  environment 
created  by  the  neutralization  of  the  excess  of  acid,  it  will  develop  its 
proteolytic  power.  The  therapeutic  administration  of  pancreatin  is, 
therefore,  justified  (Long10). 

The  activated  trypsin  acts  on  proteins  in  very  much  the  same  way  as 
pepsin,  except  that  the  decomposition  of  the  peptone  and  proteoses  into 
polypeptides  is  the  chief  feature  of  the  process.  Thus,  after  tryptic 
digestion  has  proceeded  for  some  time,  only  a  trace  of  primary  proteoses 
but  considerable  quantities  of  leucine,  tyrosine  and  other  amino  acids 
will  be  found  present.  Some  investigators  believe  that  the  thorough 
nature  of  the  digestive  action  of  activated  pancreatic  juice  may  depend 
on  its  also  containing  erepsin,  an  enzyme  which  we  shall  see  to  be  pres- 
ent in  considerable  amount  in  the  mucous  membrane  of  the  intestine  and 
other  tissues,  and  whose  particular  function  is  to  split  polypeptides  into 
the  amino  acids.  From  the  autolytic  digestion  which  takes  place  in 
organs  kept  in  a  sterile  condition  after  death,  tryptic  digestion  differs 
in  that  it  produces  only  small  quantities  of  ammonia.  The  large  quanti- 
ties of  ammonia  produced  in  autolytic  digestion  no  doubt  have  a  rela- 
tionship to  the  acids  simultaneously  set  free  during  this  process. 

In  the  products  of  tryptic  dujcstion  it  is  usually  found  that,  although 
there  has  been  considerable  splitting  of  the  protein  into  amino  acids, 
there  are  still  a  good  many  amino-carboxyl  (XHOO)  linkages  left  un- 
broken, indicating  that  certain  polypeptides  are  left  intact  in  the  mix- 
ture. To  split  the  polypeptides  requires  the  aid  of  the  erepsin,  which  is 
present  in  the  mucous  membrane  of  the  intestine.  Interesting  inves- 
tigations have  been  made  on  the  exact  degree  to  which  trypsin-entero- 
kinase  can  split  up  the  various  known  polypeptides.  This  seems  to 
depend  on  the  structure  of  the  polypeptide  molecule  and  on  the  number 
of  amino  acids  present  in  the  chain.  For  example,  analylglycine,  but 
not  glycylalanine  is  hydrolyzed,  although  both  contain  the  same  amino 
acids  but  linked  together  in  a  different  way ;  and  tetraglycylglycine, 
which  contains  five  glycine  radicles,  is  hydrolyzed,  whereas  diglycylgly- 
cine,  which  contains  only  three,  is  not. 


THE    BIOCHEMICAL   PROCESSES   OF   DIGESTION  491 

The  importance  of  the  presence  of  ercpsin  in  the  mucous  membrane 
of  the  intestine  is  thai  it  serves  as  a  barrier  to  the  passage  of  any  unsplit 
amino  acids  from  the  intestinal  contents  into  the  blood.  It  insures  the 
breaking  up  of  the  protein  molecule  into  its  ultimate  units  before  absorp- 
tion. The  further  fate  of  the  absorbed  amino  acids  will  be  considered 
under  the  subject  of  protein  metabolism. 

The  Actiox  of  Lipase 

Neutral  fat  is  decomposed  into  fatty  acids  and  glycerine  by  the  lipase 
present  in  the  pancreatic  juice.  This  enzyme  may  also  be  extracted  from 
the  glands  by  means  of  60  per  cent  alcohol.  Its  action  is  remarkably 
accelerated  by  the  presence  of  bile,  and  considerably  depressed  by  inor- 
ganic salts.  It  is  also  very  dependent  on  the  degree  of  alkalinity,  the 
optimum  being  a  hydrogen-ion  concentration  of  H  x  108.  The  favoring 
action  of  bile  is  undoubtedly  owing  to  the  bile  salts  (see  page  493),  and 
it  is  probable  that  this  action  is  dependent  upon'  the  influence  which 
these  have  in  lowering  surface  tension  and  therefore  bringing  about  a 
more  intimate  contact  between  fat  and  water. 

The  Action  of  Amylopsin 

The  action  of  pancreatic  juice  on  carbohydrates  depends  on  the 
amylolytic  enzyme  .called  amylopsin.  In  animals  having  no  active  ptyalin 
in  the  saliva,  amylopsin  serves  as  the  only  diastatic  enzyme  concerned 
in  the  digestive  process.  In  any  case,  at  least  for  the  first  stages  of  the 
disruption  of  the  starch  molecule — that  is,  its  conversion  into  dextrines — 
amylopsin  is  a  more  powerful  enzyme  than  ptyalin.  It  does  not  appear 
to  be  so  efficient  as  ptyalin  in  the  final  stages  of  the  hydrolysis,  for  it 
does  not  produce  so  much  reducing  sugar  as  ptyalin  does.  Indeed  ex- 
tracts of  pancreas  will  sometimes  convert  starch  into  soluble  starch  and 
dextrine  with  great  speed,  but  produce  scarcely  any  reducing  sugar. 
On  this  account  it  is  believed  by  many  investigators  that  there  are  at  least 
two  distinct  and  separate  enzymes  in  amylopsin  and  also  perhaps  in 
ptyalin,  one  a  true  amylase,  which  converts  starch  into  dextrine,  and 
the  other  a  dextrinase,  which  converts  dextrine  into  maltose.  In  the 
case  of  both  ptyalin  and  amylopsin  digestion  proceeds  best  in  a  very 
weak  acid  reaction.  Amylopsin,  as  it  is  secreted  in  the  pancreatic  juice, 
is  fully  activated ;  bile,  apart  from  the  alkali  which  it  contains,  having 
no  influence  on  its  digestive  power. 

Besides  amylopsin  the  pancreatic  juice  also  contains  maltase,  and  in 
the  case  of  young  animals  or  of  those  that  take  milk  with  their  food 
throughout  their  lives,  lactase  also.     After  the  suckling  animal  has  dis- 


492  DIGESTION 

continued  taking  milk,  the  lactase  disappears  from  the  pancreatic  juice. 
Attempts  have  been  made  to  bring  it  back  by  feeding  the  adult  upon 
milk,  but  without  success.  Occasionally  the  pancreatic  juice  also  con- 
tains invertase. 

The  Bile 

Associated  with  the  pancreatic  juice  in  all  its  functions  is  the  bile. 
When  this  fluid  is  prevented  from  entering  the  intestine,  the  digestive 
process  becomes  very  imperfect,  the  absorption  of  fat  being  particularly 
interfered  with  (see  page  691).  Bile  is  also  an  excretory  product,  and 
its  composition  therefore  is  much  more  complex  than  that  of  the  other 
digestive  fluids.  This  varies  very  much,  however,  according  to  the 
method  of  collection.  Bile  from  the  gall  bladder  after  death  contains 
much  more  solid  material,  particularly  bile  salts  and  mucin,  than  that 
collected  from  a  fistula  of  the  bile  duct  or  gall  bladder  during  life. 
These  differences  will  be  evident  from  the  accompanying  table. 

Bile  from 
Gall  bladder  Fistula 

100  parts  contain — ■ 

Water    86  97 

Solids    14  3 

Organic  salts   (bile  salts) 9  0.9-1-8 

Mucin  and  bile  pigment 3  0.5 

Cholesterol     0.2  0.06-0.16 

Lecithin  and  fat 0.5-1.0  0.02-0.09 

Inorganic   salts    0.8  0.7-0.8 

In  general  it  may  be  said  that  bile  obtained  from  a  fistula  in  man 
contains  only  about  3  per  cent  of  total  solids,  of  which  from  one-fourth 
to  one-half  are  inorganic,  whereas  bile  from  the  gall  bladder  contains 
10  to  20  per  cent  of  total  solids,  of  which  only  about  one-twentieth  are 
inorganic.  The  chief  cause  for  this  difference  appears  to  be  that  when 
the  bile  goes  to  the  intestine,  a  considerable  proportion  of  its  bile  salts 
is  reabsorbed  into  the  portal  blood  and  reexcreted  by  the  liver.  Some 
of  the  difference  may  also  be  caused  by  the  fact  that  absorption  of 
water  takes  place  from  the  gall  bladder,  and  that  mucin  and  possibly 
cholesterol  are  secreted  by  this  organ.  These  striking  differences  be- 
tween fistula  and  gall-bladder  bile  are  observed  only  Avhen  the  com- 
mon bile  duct  is  occluded.  If  the  bladder  fistula  is  made  with  the  com- 
mon duct  left  open,  some  of  the  bile  gains  entry  to  the  duodenum  and 
therefore  becomes  reexcreted.  It  is  well  known  that  a  fistula  of  the  gall 
bladder  in  man  after  a  time  closes  up  and  the  bile  again  takes  its  usual 
course  along  the  bile  duct  into  the  duodenum. 


THE    BIOCHEMICAL    PROCESSES   OF   DIGESTION  493 

Interesting  observations  have  been  collected  on  the  amount  of  the  secre- 
tion from  a  fistula  Loth  in  man  and  in  the  lower  animals.  In  man  it  is 
commonly  staled  that  about  500  c.c.  of  bile  are  secreted  daily,  the 
amount  varying  considerably  during  the  different  hours  of  the  day.  The 
secretion  of  bile  is  greatly  reduced  by  hemorrhage.  It  is  greater  on  a 
meat  diet  than  on  one  of  carbohydrates.  It  is  reduced  during  starva- 
tion, but  continues  to  be  secreted  up  to  the  moment  of  death. 

Functions  of  Bile 

One  of  the  main  functions  of  the  bile  salts  is  that  they  greatly  assist, 
not  onjy  in  the  digestion,  but  also  in  the  absorption  of  fats.  When  bile 
is  excluded  from  the  intestine,  the  feces  are  loaded  with  fatty  acids 
which  have  been  split  off  partly  by  the  now  less  effective  lipase  and 
partly  by  the  action  of  bacteria.  The  fatty  acid  thus  liberated  in  the 
absence  of  bile  salts  is  not  absorbed,  because  the  bile  salts  serve  as  the 
carriers  of  fatty  acids  into  the  epithelial  cells  and  lacteals.  They  com- 
bine with  the  fatty  acids,  probably  by  forming  some  chemical  compounds, 
in  which  they  carry  them  into  the  endothelial  cells  where  the  compounds 
become  disrupted,  the  fatty  acid  combining  with  glycerine  to  again  form 
neutral  fat  and  the  bile  salts  being  carried  to  the  liver  and  reexcreted. 
The  influence  of  bile  salts  in  assisting  the  action  of  lipase  is  probably 
due  to  a  lowering  of  the  surface  tension,  thus  bringing  water  and  fat 
into  closer  union.  This  accelerating  influence  has  also  been  demonstrated 
when  synthetic  bile  salts  have  been  used,  showing  clearly  that  it  is  really 
these  and  not  any  other  constituent  of  the  bile  that  are  responsible  for 
its  accelerating  influence. 

Bile  also  functionates  as  a  regulator  of  intestinal  putrefaction.  This 
it  does  apparently  because  of  its  slight  laxative  properties,  by  which 
the  intestinal  contents  are  expelled  before  the  bacteria  have  grown  to 
any  great  extent  in  them.  Bile  itself  is  a  favorable  culture  medium  for 
certain  bacteria,  so  that  it  can  have  no  antiseptic  action.  Its  assistance 
in  the  action  of  trypsin  and  amylopsin  depends  very  largely  upon  the 
alkali  which  it  contains. 

As  an  excretory  vehicle  bile  is  important,  because  it  possesses  the 
power  of  dissolving  cholesterol.  Toxins  and  metallic  poisons  of  various 
kinds  are  also  excreted  in  it. 

Although  not  directly  concerned  with  the  digestive  function,  it  will  be 
convenient  to  say  something  here  concerning  the  chemical  nature  and 
derivation  of  the  various  biliary  constituents. 


494  DIGESTION 

THE  CHEMISTRY  OF  BILE 

The  Bile  Salts 

In  most  animals  the  bile  salts  consist  of  the  sodium  salts  of  glycoeholic 
and  tanrocholic  acids.  Each  of  these  acids  is  composed  of  a  part  called 
cholic  acid  which  is  more  or  less  related  to  cholesterol,  and  of  glycine 
(CH2NH2COOH  amino-acetic  acid)  or  taurine  (C,H-XS03),  a  derivative 
of  cysteine,  which  is  a-amino-/?-thiopropionic  acid  (CH,HS.CHXH2. 
COOH).  The  exact  form  of  cholic  acid  varies  in  different  animals,  that 
of  the  pig,  for  example,  being  different  from  that  of  man.  Bile  salts  are 
an  exclusive  product  of  liver  metabolism;  i.e.,  they  are  not  formed  in 
any  other  part  of  the  animal  body.  They  give  a  very  sensitive  color 
reaction  known  as  Pettenkofer's,  which  however  is  not  specific  of  bile  acids, 
since  it  is  also  given  by  oleic  acid  and  by  many  aromatic  substances  and 
alcohols.  It  must  be  remembered  that  the  part  of  the  bile  salts  that  is 
characteristic  of  the  liver  is  the  cholic  acid,  the  taurine  and  glycine 
being  present  in  other  tissues  and  organs. 

When  cholic  acid  is  given  to  animals  mixed  with  the  food,  the  amount 
of  taurocholic  acid  excreted  with  the  bile  is  increased,  indicating  that 
there  must  be  a  store  of  taurine  available  in  the  organism.  This  store 
can  not,  however,  be  large,  for  if  the  feeding  with  cholic  acid  is  repeated 
several  times,  it  will  be  found  that  the  taurocholic  acid  diminishes  and 
glycoeholic  acid  takes  its  place ;  and  this  increased  excretion  of  glyco- 
eholic acid  goes  on  just  as  long  as  cholic  acid  is  fed.  The  reserve  of 
taurine  in  the  animal  body  appears  therefore  to  be  limited,  although  it  is 
used  in  preference  to  glycine  when  there  is  an  excess  of  cholic  acid  to  be 
neutralized.  On  the  other  hand,  the  store  of  glycine  seems  to  be  inexhaust- 
ible. That  there  is  no  reserve  of  cholic  acid  itself  in  the  body  is  indicated  by 
the  fact  that  no  increase  in  taurocholic  acid  excretion  by  the  bile  results 
when  cystine,  the  mother  substance  of  taurine,  is  given  with  the  food. 
If  both  taurine  and  cholic  acid  be  fed,  however,  the  excretion  of  tauro- 
cholic acid  increases. 

The  relative  amounts  of  taurocholic  and  glycoeholic  acids  in  the  bile  of 
different  animals  differ  considerably.  Human  bile  contains  relatively 
a  small  amount  of  taurocholic  acid;  on  the  other  hand,  the  bile  of  the  dog 
contains  a  large  excess  of  it. 

Cholesterol 

In  human  bile  the  percentage  of  this  important  substance  is  not  high 
(1.6  parts  per  1000),  but  it  is  of  great  clinical  importance  because  of  the 
fact  that  it  may  separate  out  as  a  precipitate  forming  gallstones.     The 


THE    BIOCHEMICAL    PROCESSES    OF    DIGESTION  40") 

percentage  of  cliolesterol  in  these  varies  from  20  to  90 ;  the  remainder 
being  organic  material  such  as  epithelial  cells,  inorganic  salts,  pigment, 
etc.  The  origin  of  cholesterol  is  partly  endogenous  and  partly  exoge- 
nous. In  the  former  case  it  comes  from  the  envelope  of  red  blood  cor- 
puscles and  from  the  nervous  tissues,  where  it  is  present  in  considerable 
amount.  The  latter  source  is,  of  course,  the  food.  The  increase  in 
cholesterol  esters  in  the  blood  after  feeding  with  food  rich  in  this  sub- 
stance has  been  shown,  particularly  in  rabbits. 

That  the  bile  should  be  the  pathway  through  which  cholesterol  is 
excreted  depends  no  doubt  on  the  fact  that  it  contains  bile  salts,  which 
along  with  their  other  properties  have  a  remarkable  solvent  action  on 
cholesterol.  This  solvent  property  depends  on  the  cholic  acid  part  of 
the  bile  salts,  which,  as  already  remarked,  is  chemically  very  closely 
related  to  cholesterol ;  indeed,  the  relationship  is  so  close  that  some  have 
suggested  that  cholic  acid  is  derived  from  cholesterol.  This  would  mean 
that  the  cholesterol  of  blood  is  excreted  in  two  ways,  as  cholesterol  and 
as  cholic  acid.  Other  observers,  however  maintain  that  the  cholesterol 
is  excreted  mainly  by  the  lining  membrane  of  the  gall  bladder,  and 
that  this  explains  why  gall-bladder  bile  contains  more  of  it  than  fis- 
tula bile.  This  evidence  is,  however,  not  very  strong,  for  the  greater 
excretion  of  cholesterol  under  conditions  where  the  circulation  of  bile 
is  going  on  may  be  explained  as  due  to  the  presence  of  bile  salts,  which 
serve  to  carry  the  cholesterol  out  of  the  blood. 

Many  problems  remain  to  be  elucidated  in  connection  with  the  metabolic 
history  of  cholesterol.  That  some  of  it  is  absorbed  when  cholesterol  is 
contained  in  the  food  might  seem  to  indicate  that  its  source  is  entirely 
exogenous.  Against  this  view,  however,  stand  two  facts:  (1)  that  the 
cholesterol  in  the  feces  of  herbivorous  animals  is  of  the  same  variety  as 
that  present  in  those  of  carnivorous  animals  and  not  the  phytosterol 
which  is  present  in  plants;  and  (2)  that  the  universal  presence  of 
cholesterol  in  cells  indicates  that  it  must  be  manufactured  there. 

The  Bile  Pigments 

The  pigments  of  bile  are  bilirubin  and  biliverdin.  The  latter  is  pro- 
duced from  the  former  by  oxidation.  If  the  oxidation  be  carried  a 
stage  further,  a  blue  pigment  called  bilicyanin  is  formed.  This  process 
of  oxidation  can  be  observed  in  the  ring  test  for  bile  pigment  with 
fuming  nitric  acid.  When  bilirubin  is  reduced,  urobilin,  one  of  the 
pigments  in  urine,  is  formed.  Bilirubin  must  therefore  be  considered 
as  the  mother  substance  of  all  these  pigments,  and  it  is  of  interest  in 
connection   with   its   derivation   to  know   that   it   has   the   same   formula 


496  DIGESTION 

as  iron-free  heniatin  or  hematoporphyrin,  which  is  produced  by  treating 
hemoglobin  with  concentrated  sulphuric  acid. 

Chemical  investigation  has  shown  that  bilirubin  is  built  up  from  sub- 
stituted pyrrols,  probably  four  such  being  contained  in  the  molecule. 
The  pyrrol  group  is  also  present  in  indole  and  tryptophane,  and  con- 
sists of  four  carbon  atoms  and  an  NH  group  linked  together  as  a  ring 
(see  page  604).  Similar  pyrrol  derivatives  can  be  produced  by  decom- 
posing chlorophyl,  the  green  coloring  matter  of  plants.  It  is  important 
to  remember  that  bilirubin  is  acid  in  nature,  and,  therefore,  can  com- 
bine with  alkalies  to  form  salts.  The  relative  amounts  of  bilirubin  and 
biliverdin  vary  in  the  bile  of  different  animals. 

When  these  pigments  enter  the  intestine  they  are  reduced  to  urobilin, 
part  of  which  passes  out  with  the  feces,  another  part  being  absorbed  into 
the  blood  and  excreted  in  the  urine.  Part  of  that  excreted  in  the  urine 
exists,  however,  as  a  so-called  chromogen  named  urobilinogen.  The 
urobilinogen  is  converted  into  urobilin  by  the  action  of  oxygen. 

The  method  by  which  urobilin  is  produced  from  blood  pigment  has 
been  studied  by  histologic  examination  of  the  liver  particularly  of  birds 
and  amphibia,  in  which  destruction  of  blood  pigment  goes  on  rapidly. 
Increased  destruction  of  blood  pigment  can  be  induced  by  poisoning 
with  certain  substances  such  as  arseniureted  hydrogen.  From  such 
studies  it  is  usually  believed  that  the  bile  pigments  are  a  peculiar  product 
of  hepatic  activity,  being  produced  from  blood  pigments  that  are  de- 
rived from  erythrocytes  which  have  been  broken  down  either  in  the  liver 
itself  or  in  some  other  viscus  (e.  g.,  the  spleen).  Whipple  and  Hooper20 
have  brought  forward  seemingly  incontrovertible  evidence  against  such 
a  view.  They  have  found,  for  example,  that  the  bile  pigments  are 
formed  just  as  readily  in  animals  in  which  the  circulation  of  the  liver 
was  greatly  curtailed  by  anastomosing  the  portal  vein  with  the  vena 
cava  (Eck  fistula)  as  in  normal  animals.  Even  when  the  circulation 
was  limited  to  the  anterior  end  of  the  animal  (head  and  thorax)  bile 
pigment  appeared  in  the  blood  when  hemolyzed  erythrocytes  were  in- 
jected, and  it  was  also  formed  when  hemoglobin  was  placed  in  the  pleural 
and  peritoneal  cavities.  The  endothelial  cells  of  the  blood  vessels  and 
elsewhere  can  evidently  form  the  pigments,  at  least  when  the  liver  is 
absent.  When  such  a  process  occurs  under  normal  conditions,  it  is  quite 
probable  that  the  liver  acts  merely  as  an  excretory  organ  for  the  pig- 
ments in  the  same  way  as  the  kidney  does  for  urea.  Possessed  of  endo- 
thelial cells,  the  liver  might  itself  also  produce  some  of  the  pigments, 
but  no  more  than  other  organs  with  a  similar  number  of  those  cells. 

Even  the  derivation  of  bile  pigments  from  hemoglobin  is  called  in 
question,  for  the  same  workers  have  observed  that,  whereas  the  excre- 


T1IK   BIOCHEMICAL    I'KOCKSSKS   OF    DIGESTION  497 

tion  of  pigment   from  a  biliary  fistula  is  remarkably  constanl  in  a  dog 

fed  on  a  fixed  mixed  diet,  it  became  increased,  sometimes  by  100  per 
cent,  when  the  diet  was  changed  to  one  of  carbohydrates,  and  depressed 
on  a  diet  of  meat.  The  question  arises  as  to  whether,  after  all,  the  bile 
pigments  are  really  derived  from  broken-down  hemoglobin.  May  they 
not   be   manufactured   de   novo   out   of  other   materials? 

Whipple  and  Hooper  have  also  shown  that  bile  is  a  most  important 
secretion,  for  dogs  rarely  survive  on  an  ordinary  diet  if  bile  is  perma- 
nently prevented  from  entering  the  intestine.  Intestinal  symptoms 
soon  supervene,  and  become  progressively  more  severe  until  the  death 
of  the  animal.  Feeding  with  bile  does  not  relieve,  the  condition,  but 
feeding  with  cooked  liver  seems  to  have  a  beneficial  effect. 

After  extravasation  of  blood  in  the  subcutaneous  tissues,  as  in  a  bruise, 
for  example,  a  decomposition  of  hemoglobin  proceeds  quite  like  that 
occurring  in  the  liver,  and  leads  to  the  production  of  blue  and  brown 
and  green  pigments  like  those  of  the  bile.  When  hemolysis  is  produced, 
as  by  inhalation  of  arseninreted  hydrogen  or  the  injection  of  inorganic 
or  biological  hemolysins,  there  is  an  immediate  increase  in  the  amount 
of  bile  pigment  in  the  bile.  Even  the  injection  of  hemoglobin  solutions 
has  this  effect.  Under  these  conditions  of  hemolysis,  besides  an  increase 
in  urobilin,  there  may  be  considerable  quantities  of  hemoglobin  secreted 
in  the  urine. 

Bile  salts  and  pigments  usually  accompany  each  other  wdien  any- 
thing occurs  to  interfere  with  the  free  secretion  of  bile.  For  example, 
after  ligation  of  the  bile  duct  both  bile  pigments  and  bile  salts  accumu- 
late in  the  blood,  in  the  serum  of  which  they  may  be  recognized  by  the 
ordinary  chemical  tests  in  from  four  to  six  hours  after  the  operation. 
If  the  accumulation  be  allowed  to  proceed  further,  the  bile  pigments 
become  deposited  in  the  tissues,  giving  them  the  peculiar  yellowish  ap- 
pearance known  as  jaundice.  Under  these  conditions  the  bile  salts  and 
pigments  also  appear  in  the  urine.  The  accumulation  of  bile  salts  in 
the  body  affects  certain  physiologic  processes;  for  one  thing,  it  causes 
a  great  lengthening  in  the  .clotting  time  of  the  blood. 

If  the  blood  supply  to  the  liver  is  interrupted  by  ligation  of  the  portal 
vein  and  hepatic  artery  at  the  same  time  that  the  bile  ducts  are  occluded, 
not  a  trace  either  of  bile  salts  or  of  bile  pigment  appears  in  the  blood 
during  the  six  to  eighteen  hours  that  the  animals  survive  the  operation. 

The  amount  of  obstruction  of  the  bile  duct  necessary  to  produce  these 
symptoms  is  very  slight,  since  bile  is  secreted  at  a  very  low  pressure. 
Even  a  clot  of  mucus  or  a  swollen  condition  of  the  mucous  membrane 
of  the  duct  is  sufficient  to  produce  obstruction.  In  the  discharge  of  bile 
from  the  gall  bladder  into  the  duodenum  it  is  claimed  by  Meltzer21  that  a 


498  DIGESTION 

reciprocal  relationship  exists  between  the  contraction  of  the  bladder 
musculature  and  the  relaxation  of  the  muscular  fibers  surrounding  the 
duct  in  the  duodenum.  If  this  reciprocal  innervation  fails  to  operate 
properly,  discharge  of  bile  into  the  duodenum  may  become  obstructed 
so  that  a  certain  amount  passes  back  into  the  blood,  as  in  cases  of  bile- 
duct  obstruction. 

Bile  also  contains  a  certain  amount  of  lecithin  and  other  phospholipid. 
The  amount  varies  considerably  in  the  bile  of  different  animals,  even  in 
animals  of  the  same  species.  It  is  probably  derived,  as  already  men- 
tioned, like  the  cholesterol,  from  the  breaking-down  of  red  blood  cor- 
puscles that  goes  on  in  the  liver.  It  is  no  doubt  digested  by  the  ferments 
of  the  intestinal  tract,  the  liberated  cholin,  since  it  is  toxic  if  absorbed, 
being  further  attacked  by  bacteria  so  as  to  become  converted  into  cer- 
tain substances  of  a  nontoxic  nature. 


CHAPTER  LVII 
BACTERIAL  DIGESTION  IN  THE,  [NTESTINE 

On  an  average  diet,  in  twenty-four  hours  the  feces  of  man  weigh 
about  100  grams,  or  after  drying,  about  20  grams.  About  one-fourth  of 
the  dry  matter  consists  of  the  bodies  of  bacteria.  If  plated  out  by  the 
ordinary  baeteriologic  methods,  however,  it  will  be  found  that  only  a 
small  proportion  of  these  bacteria  are  living.  The  greater  number  have 
been  destroyed,  probably  by  the  action  of  the  mucin  in  the  large  intes- 
tine. The  nitrogen  content  of  the  feces  amounts  to  about  1.5  grams  a 
day,  of  which  about  one-half  is  bacterial  nitrogen.  If  the  diet  contains 
large  quantities  of  cellulose  material,  as  in  green  vegetable  food  and 
fruit,  the  mass  of  feces  as  well  as  the  bacterial  content  may  be  consid- 
erably greater. 

The  foregoing  facts  indicate  that  very  extensive  baeteriologic  proc- 
esses must  be  going  on  all  the  time  in  the  intestinal  contents,  and  the 
question  arises  as  to  whether  such  action  is  beneficial  or  otherwise  to  the 
animal  economy.  To  answer  this  question  interesting  observations  have 
been  made  on  the  growth  and  well-being  of  animals  excised  from  the 
uterus  under  strictly  sterile  conditions  and  maintained  thereafter  on 
sterile  food.  Such  observations  made  on  guinea  pigs  have  shown  that 
the  animals  thrive  and  grow  perfectly  for  a  considerable  time.  Experi- 
ments carried  out  on  chicks  have  not,  however,  yielded  similar  results. 
Chicks  hatched  out  from  the  egg  under  strictly  sterile  conditions  and 
then  fed  on  sterile  grain,  do  not  thrive,  but  do  so  if  with  the  grain  is 
mixed  a  certain  amount  of  fowl  excrement.  These  experiments,  appar- 
ently contradictory  in  their  results,  show  that  for  certain  groups  of 
animals  bacteria  are  required,  but  not  for  others. 

The  difference  is  probably  dependent  on  the  nature  of  the  foods.  It 
will  be  remembered  that  the  size  of  the  large  intestine  varies  consider- 
ably according  to  the  nature  of  the  diet  (see  page  463).  Animals  taking 
great  quantities  of  cellulose  foodstuffs  have  very  large  ceca  and  very 
long  large  intestines;  whereas  those  which,  like  the  cat,  live  practically 
entirely  on  cellulose-free  food,  have  a  rudimentary  large  intestine.  The 
size  of  the  lower  intestine  is  obviously  dependent  on  the  presence  or 
absence  of  cellulose  in  the  food.  It  will  be  remembered  also  that  the 
forward  movement  of  the  contents  of  the  large  intestine  is  very  slow ; 
indeed,  special  provision  is  made,  by  the  presence  of  the  so-called  anti- 

499 


500  DIGESTION 

peristaltic  wave,  to  delay  its  movement.  This  suggests  that  an  important 
digestive  process  must  be  proceeding  in  this  part  of  the  gut.  In  these 
ways  conditions  become  established  in  the  cecum  for  the  active  opera- 
tion of  bacteria.  They  attack  the  cellulose,  and  liberate  the  more  diges- 
tible foodstuffs  contained  in  the  vegetable  cells,  also  producing  out  of 
the  cellulose  itself  materials  of  nutritive  value.  The  acids  that  are  also 
produced  by  this  process  are  neutralized  by  the  carbonates  secreted 
by. the  mucosa. 

In  certain  herbivorous  animals — the  ruminants — this  process  in  the 
cecum  is  not  relatively  of  such  importance,  because  it  takes  place  in  the 
paunch.  The  animals  swallow  the  food  and  it  mixes  in  this  part  of  the 
stomach  with  the  saliva,  so  that  bacteria  and  ferments  contained  in  it, 
called  cytases,  attack  the  cellulose,  liberating  the  more  easily  digested 
foodstuffs  inclosed  within  the  cell  walls.  As  this  process  goes  on  acids 
accumulate  in  the  digestive  mixture.  The  food  is  then  returned  to  the 
mouth,  chewed  over  again,  and  swallowed  again  into  the  main  stomach, 
where  it  is  digested.  The  aid  which  bacteria  render  to  digestion  depends 
therefore  on  the  nature  of  the  diet.  Man,  being  omnivorous,  stands  mid- 
way between  the  two  groups  of  animals  discussed  above.  Although  the 
cellulose  contained  in  his  food  is  not  itself  sufficiently  digested  to  furnish 
nutriment,  yet  it  is  so  far  acted  upon  as  to  permit  the  rupture  of  the 
cell,  the  contents  of  which  are  then  digested.  The  cellulose  is,  however, 
of  value  in  furnishing  bulk  to  the  intestinal  contents — "intestinal  bal- 
last," it  is  sometimes  called. 

In  the  small  intestine  in  man  there  are  bacteria  capable  of  acting  on 
carbohydrates  and  producing  from  them  organic  acids,  such  as  lactic, 
acetic,  etc.  So  long  as  a  sufficiency  of  carbohydrate  exists  to  encourage 
the  action  of  these  bacteria,  others  having  an  action  on  protein  do  not 
seem  to  thrive.  It  may  be  that  this  is  to  be  accounted  for  partly  by  the 
production  of  acid  substances  by  the  carbohydrate  fermentation,  and 
partly  by  the  fact  that,  as  soon  as  the  protein  molecule  is  broken 
down  by  the  digestive  enzymes,  its  building-stone  amino  acids  are  ab- 
sorbed. There  are  probably  also  bacteria  in  the  small  intestine  capable 
of  splitting  fat  into  fatty  acid  and  glycerine,  but  practically  nothing  is 
known  of  their  action.  In  the  large  intestine  of  man,  along  with  the 
cellulose-digesting  bacteria  already  mentioned,  protein-digesting  bac- 
teria are  also  present.  These  bacteria  belong  to  the  class,  Bacillus  coli 
communis,  the  various  members  of  which  are  known  as  faculative  anae- 
robes because  they  can  grow  in  the  presence  or  absence  of  oxygen. 

If  bacterial  growth  is  excessive  or  there  is  an  insufficiency  of  carbohy- 
drates in  the  small  intestine,  the  bacteria  attack  the  amino  acids  pro- 
duced by  the  digestive  enzymes  and  decompose  them  into  products 
that  may  be  toxic  if  absorbed  into  the  blood. 


BACTERIAL   DIGESTION    IN    THE    INT)  SUM  501 

Bacterial  Digestion  of  Protein 

From  a  pathologic  standpoint,  the  most  important  action  of  bacteria 
is  that  which  takes  place  on  protein.  Under  anaerobic  conditions  the 
intestinal  bacteria  have  in  general  the  power  of  splitting  off  the  amino 
group  whereas  under  aerobic  conditions  they  split  off  the  carboxyl 
group.  This  splitting  off  of  the  carboxyl  group  as  carbon  dioxide  is  per- 
formed by  the  so-called  carboxylase  bacteria,  and  it  may  take  place  eithei 
before  or  after  deamidization  (see  page  615).  If  it  happens  after  this 
process,  the  products  are  not  highly  toxic  and  include  phenol,  cresol, 
indole  and  skatole,  which  are  partly  absorbed  into  the  blood  and  partly 
excreted  with  the  feces. 

The  fractions  of  those  substances  that  are  absorbed  into  the  blood 
have  their  toxicity  removed  by  conjugation  mainly  with  sulphuric  acid 
to  form  the  so-called  ethereal  sulphates.  A  part  is  also  combined  with 
glycuronic  acid  (see  page  632).  In  the  case  of  phenol  and  cresol  this 
conjugation  occurs  immediately  after  absorption,  but  in  the  case  of 
indole  and  skatole  it  is  preceded  by  an  oxidative  process,  converting 
these  substances  into  indoxyl  and  skatoxyl  respectively.  The  detoxica- 
tion  process  occurs  in  the  liver,  as  has  been  shown  by  experiments  in 
which  this  organ  was  artificially  perfused  outside  the  body.  They  are 
then  removed  from  the  blood  by  the  kidneys  and  excreted  in  the  urine. 
The  proportion  of  ethereal  sulphates  in  this  fluid  is  therefore  an  indica- 
tion of  the  extent  of  intestinal  putrefaction  of  protein  (see  page  632). 
The  indican,  being  readily  detectable  by  the  well-known  color  reaction 
of  Jaffe,  serves  as  an  indicator  of  the  extent  of  intestinal  putrefaction. 
The  indole  and  skatole  which  are  not  thus  absorbed  and  detoxicated  are 
excreted  with  the  feces,  to  which  they  give  the  characteristic  odor. 

The  source  of  the  phenol  is  tyrosine  and  that  of  the  indole  is  trypto- 
phane. The  chemical  processes  involved  are  shown  in  the  following 
equations,  in  which  the  by-products  of  the  reactions  are  in  brackets. 

C.OH  COH  COH  COH  COH 

//\  //\  //\  //\  //\ 

HC    CH       HC    CH       HC    CH       HC    CH       HC    CH 

I     II  I     H  I     II  I    II  I     II 

HC    CH       HC    CH       HC    CH       HC    CH       HC    CH 

\/  \/  \/  \/  \/ 

C  C  C  C  CH 


CH,  CH2  CH,                               CH3(CO,  +  H20) 

|  (XH3)       |            (C02+H20)     |  (C02) 

CHXH.,  CH.  COOH 

I            "  I 

COOH  COOH 

(tyrosine)  (p-oxyphenyl-  (p-oxyphenyl-                 (paracresol)             (phenol) 

propionic  acid)  acetic  acid) 


502  DIGESTION 

Putrefaction   <>i'  tryptophane    is    probably   preceded  by   deamidizaticm 

CH  CH 

//\                                                                                        /\ 
HC         C C— CH.,.CHNH,.COOH  HO         C 0— CH„CH,.COOH 


HO         C        CH  (NH3)  HC        C        CH  (C02  +  H20) 

CH       NH  CH      NH 

(tryptophane)  (indole-propionic  acid  | 

CH  CH  CH 

//\  //\  //\ 

HC        C C— CH...COOH  HC         C — -CH  HC         C— — C— CH, 

I         il        I!  >       I         II        II  I         II        II 

HC        C         CH         (CO.  +  H,0)  HC        C         CH  HC         C        C 

\/\/  \/\/  \/\/ 

CH       NH  CH      NH     (+CH3)         CH      NH 

(iudole-acetic  acid)  (indole)  (skatole) 

If,  however,  the  carboxylase  bacteria  remove  the  carboxyl  group  be- 
fore the  amino  group  has  been  removed,  highly  toxic  substances  called 
amines  are  produced.  They  are  the  so-called  ptomaines.  From  alanine, 
ethylamine  is  formed;  from  tyrosine,  phenolethylamine;  from  histidine, 
which  it  will  be  remembered  is  an  important  protein  building-stone, 
imidazylethylamine,  and  so  on.  The  process  of  formation  is  illustrated 
in  the  accompanying  formulae: 

1.  CH3.CH(NH2).COOH  =  CO,  f  CH3.CH2(NH,) 

Alanine  Ethvlamine 

2.  CsH4(OH).CH;.CH(NH2).COOH  =  C02  +  C6H4(OH).CH,.CH2.NH2 

Tyrosine  Phenylethylamine 

3.  C3NJI3.CH2.CH(NH2).COOH  =  CO. -f  CaH3N2.  CH2.CH,.NH2 

Histidine.  Imidazylethylamine. 

Similar  substances  are  very  common  in  the  metabolic  products  of 
plants ;  for  example,  they  constitute  the  active  principle  of  ergot.  They 
are  also  no  doubt  produced  in  the  tissues  of  mammals,  imidazylethyla- 
mine, commonly  called  histamine,  being  thus  produced,  as  well  as  the 
closely  related  epinephrine,  which  is  the  active  principle  of  the  supra- 
renal gland  (see  page  737),  and  may  be  described  as  a  methylated  ethyla- 
mine derivative  of  tyrosine. 

Phenylacetic  acid  produced  by  a  similar  process  from  tyrosine  may 
be  excreted  in  the  urine,  where  it  forms  the  mother  substance  of  homo- 
gentisic  acid,  to  which  the  dark  brown  color  of  the  urine  in  alkaptonuria 
is  due. 

The  great  importance  attached  to  these  decomposition  products  of 
proteins  depends  on  the  fact  that  they  have  powerful  pharmacologic 
actions.  These  actions  are  developed  very  largely  upon  the  vascular 
system;  histamine,  for  example,  produces  marked  vasodilatation  and 
lowers  the  coagulability  of  the  blood,  whereas  other  substances  of  the 


BACTERIAL   DIGESTION    IN'    THE    INTESTINE  503 

same  class,  like  epinephrine,  have  the  property  of  raising  the  blood  pres- 
sure. In  larger  doses,  serious  nervous  symptoms  and  a  condition  of  pro- 
found collapse  are  produced.  These  observations  have  led  several  inves- 
tigators to  believe  that  the  persistent  occurrence  of  bacterial  fermen- 
tation and  the  absorption  of  the  resulting  decomposition  products  of 
protein  into  the  blood  ultimately  cause  arteriosclerosis  and  the  other  symp- 
toms that  accompany  senescence.  It  is  difficult  at  the  present  time  to 
know  how  much  of  this  one  ought  to  believe,  although  it  can  not  be 
doubted  that  putrefaction  has  an  unfavorable  action  on  the  arteries, 
and  that  an  excessive  degree  of  it  causes  the  symptoms  of  ptomaine 
poisoning. 

If  the  ptomaines  have  formed  in  the  food  before  it  is  eaten,  the  symp- 
toms develop  in  from  one  to  five  hours  after  the  meal,  but  if  the  decomposi- 
tion occurs  in  the  intestine  on  account  of  bacteria  that  are  taken  at  the  same 
time  as  the  food,  the  ptomaines  may  not  have  developed  sufficiently  to 
cause  symptoms  until  from  twelve  to  forty-eight  hours;  sometimes,  how- 
ever, they  develop  in  an  hour  or  so.  Prominent  among  the  symptoms  is 
usually  diarrhea,  which  develops  for  the  purpose  of  getting  rid  of  the 
offending  bacteria  and  ptomaines. 

Actual  infection  of  food  with  bacteria  of  the  paratyphoid-enteritidis 
type  is  much  more  common  than  poisoning  by  substances  {ptomaines)  that 
have  been  generated  in  food  before  it  is  taken  (Jordan17).  Meat,  milk 
and  other  protein  foods  are  usually  the  carriers  of  the  bacilli,  and  in  most 
of  the  accurately  recorded  cases  the  meat  or  milk  was  found  to  be 
derived  from  animals  suffering  from  enteritis  or  some  other  infection. 
Sometimes,  however,  perfectly  good  food  may  become  infected  by 
handling.  Although  the  symptoms  are  usually  acute,  they  may  closely 
simulate  those  of  typhoid  fever,  and  the  effects  of  the  attack  may  linger 
for  weeks  or  months. 

Botulism 

The  commonest  type  of  poisoning  by  substances  actually  present  in  the 
food  is  that  known  as  botulism.  In  this  the  gastrointestinal  symptoms 
are  not  pronounced, — indeed,  paralysis  of  the  intestinal  tract  with  con- 
stipation is  the  rule, — but  those  affecting  the  nervous  system,  dizziness, 
diplopia  and  other  visual  disturbances,  with  difficulty  in  swallowing, 
are  very  prominent.  The  temperature  arid  pulse  are  usually  normal. 
In  practically  all  of  the  reported  cases  of  botulism,  the  source  of  infection 
has  been  food  which  after  having  been  subjected  to  some  preliminary  treat- 
ment, such  as  smoking,  pickling,  or  canning,  had  been  allowed  to  stand 
for  some  time  and  then  eaten  without  cooking.  The  Bacillus  botulinus, 
which  is  responsible  for  the  production  of  the  poisons  or  toxins,  is  a 


504  DIGESTION 

strict  anaerobe  and  is  readily  destroyed  by  cooking,  as  are  also  the 
poisons.  Antitoxins  are  formed  by  sublethal  injections.  Another  but 
now  very  rare  example  of  poisoning  by  products  formed  in  food  is 
that  caused  by  "ergotoxin." 

The  treatment  in  such  cases  is  to  encourage  diarrhea  by  giving  pur- 
gatives. If  the  intoxication  is  of  a  more  chronic  character,  the  symptoms 
are  vague,  consisting  of  drowsiness,  lassitude,  headache,  and  general  de- 
pression. The  treatment  here  also  is  to  clear  out  the  intestines  by  a 
good  purge.  There  can  be  little  doubt  that  many  of  the  unhealthy  condi- 
tions of  the  skin  leading  to  the  formation  of  pimples,  acnes,  and  boils, 
are  also  caused  by  chronic  intoxication  with  protein  decomposition  prod- 
ucts.   Again,  purgation  is  the  proper  treatment. 

It  is  unnecessary  in  a  work  of  this  character  to  go  further  into  these 
highly  important  questions.  It  is  probable,  however,  that  the  importance 
of  the  relationship  of  excessive  protein  putrefaction  in  the  intestine  to 
many  of  the  so-called  minor  diseases  can  not  be  overemphasized.  On  the 
other  hand,  we  must  be  careful  not  to  attribute  every  sort  of  chronic 
condition  to  this  putrefaction.  Toxemia  is  often  a  shibboleth  of  the 
profession.  When  a  chronic  disease  can  not  be  diagnosed,  it  is  put  down 
as  a  toxemia.  This,  however,  is  not  medical  science — it  is  medical  shirk- 
ing. It  is  certainly  unsafe  at  the  present  time  to  conclude  that  the 
ordinary  symptoms  of  senescence,  such  as  hard  arteries  or  increased  blood 
pressure,  are  invariably  to  be  attributed  to  this  cause.  It  will  be  re- 
membered that  Metchnikoff  is  largely  responsible  for  such  a  view,  and 
also  that  he  suggested,  as  the  surest  way  to  ward  off  the  chance  of  such 
intoxication,  the  taking  of  buttermilk,  which  would  supply  bacteria 
through  whose  growth  in  the  intestine  the  protein-destroying  bacteria 
would  not  be  able  to  thrive.  It  is  probable  that  the  same  result  could  be 
attained  in  patients  showing  undoubted  signs  of  suffering  from  intestinal 
putrefaction  by  a  change  in  diet  in  the  direction  of  giving  more  carbo- 
hydrate, for,  as  we  have  seen,  if  there  is  a  plentiful  supply  of  this  food- 
stuff in  the  small  intestine,  the  bacteria  do  not  tend  to  attack  the  protein. 

Before  leaving  this  subject  it  is  interesting  to  consider  for  a  moment 
the  cause  of  the  severe  symptoms  that  follow  intestinal  obstruction. 
This  question  has  recently  been  diligently  investigated  by  Whipple,18 
who  found  that  the  nonprotein  nitrogen  of  blood  (page  606)  becomes  greatly 
increased  in  intestinal  obstruction.  The  cause  for.  this  increase  in  non- 
protein nitrogen  is  found  to  be  an  excessive  breakdown  of  tissue  protein 
caused  by  the  absorption  into  the  blood  of  a  proteose.  When  this  pro- 
teose isolated  from  obstructed  loops  of  intestine  was  injected  into  fast- 
ing dogs,  profound  symptoms  of  depression  were  produced,  followed,  in 
cases  in  which  the  dose  was  sublethal,  by  recovery  in  from  twenty-four 


BACTERIAL   DIGESTION   IN   THE   INTESTINE  505 

to  forty-eight  hours.  Along  with  these  symptoms  the  nitrogen  elimina- 
tion by  the  urine  increased  by  100  per  cent.  A  very  interesting  fact  is 
thai  animals  can  be  rendered  immune  to  this  proteose  by  progressively 
increasing  periodic  administration.  When  they  are  thus  immunized, 
the  toxic  symptoms  do  not  follow  upon  its  injection,  nor  are  the  symp- 
toms produced  by  artificially  creating  an  intestinal  obstruction.  Con- 
versely, when  a  chronic  toxic  condition  is  kept  up  by  a  partial  obstruc- 
tion, such  as  that  produced  by  making  a  gastrojejunal  fistula  and  occlud- 
ing the  duodenum,  the  animals  are  less  susceptible  than  normal  ones  to 
proteose  injection. 

"We  have  here  and  there  incidentally  referred  to  the  reaction  of  various 
parts  of  the  gastrointestinal  contents,  but  we  would  call  attention  once 
again  to  this  important  subject,  especially  since  many  points  of  uncer- 
tainty have  recently  been  cleared  up  by  the  accurate  observations  of 
Long  and  Fenger,19  who  used  the  electrometric  method  for  measuring 
the  hydrogen-ion  concentration.  The  contents  of  the  duodenum  removed 
by  means  of  the  Rehfuss  tube  in  man  showed  a  reaction  varying  from  dis- 
tinctly acid  to  slightly  acid,  depending  upon  the  proximity  of  the  tube 
to  the  pylorus  or  papilla,  this  position  being  determined  by  x-ray  exam- 
ination. The  slight  degree  of  alkalinity  is  surprising.  Lower  down  in 
the  duodenum  the  reaction  was  as  frequently  acid  as  alkaline,  the  de- 
gree of  acidity,  however,  being  so  slight  as  to  favor  rather  than  retard 
the  digestive  powers  of  the  pancreatic  juice. 

To  determine  the  reaction  lower  down,  the  observations  were  made  on 
recently  slaughtered  animals  (pigs,  calves,  and  lambs),  the  small  intes- 
tine being  tied  off  in  loops  of  the  upper,  middle,  and  lower  thirds.  The 
contents  of  the  last  loop  were  often  alkaline,  but  might  be  more  acid  even 
than  those  of  the  first,  which  were  usually  faintly  of  this  reaction.  Con- 
siderable variations  were,  however,  the  rule.  The  mixed  intestinal  con- 
tents of  a  recently  fed  dog,  removed  immediately  after  death,  gave 
PH  =  6.79 ;  i.  e.,  very  faintly  acid. 

DIGESTION  REFERENCES 
(Monographs) 

iPavlov,  J.  P. :  The  Working  of  the  Digestive  Glands.  Trans,  by  Sir  W.  H.  Thomp- 
son, London,  Griffin,  ed.  2,  1910. 

2»Starling,  E.  H. :  Recent  Advances  in  the  Physiology  of  Digestion,  W.  T.  Keene  & 
Co.,  Chicago,  1907. 

2Cannon,  W.  B.:  The  Mechanical  Factors  of  Digestion,  Internat.  Med.  Monographs, 
London,  Ed.  Arnold,  1911. 

4Carlson,  A.  J.:  The  Control  of  Hunger  in  Health  and  Disease,  Univ.  of  Chicago 
Press,  1917. 

5Todd,  T.  Wingate:  The  Clinical  Anatomy  of  the  Gastrointestinal  Tract,  Manches- 
ter, Univ.  Press,  1915. 


506  DIGESTION 

(Original  Papers) 

eCannon,  W.  B.,  and  Cattell,  McKeen:     Am.  .Jour.  Physiol.,  1916,  xli,  39. 

caGesell,  R.:     Proc.  Am.  Physiol.  Soe.,  Am.  Jour.  Physiol.,  1918,  xlv,  559. 

^Dale,  H.  H.,  and  P.  P.  Laidlaw:     Proc.  Phvs.  Soc,  Jour.  Physiol.,  1912,  xliv,  pp. 
12,  13.  '  '  ' * 

TaBabkin,  B-.  P.,  Rubaschkin,  W.  J.,  and  Ssawitsch,  W.  W.:     Arch.  f.  mikr.  Anatomic, 
1909,  lxxiv,  68. 

?Macallum,  A.  B.:     Ergeb.  der  Physiol.,  xi,  598-657. 

^Miller,  F.  R.:     Quart.  Jour.  Exper.  Physiol.,  1913,  vi,  57. 
iflEdkins,  J.  S.:     Jour.  Physiol.,  1906,  xxxiv,  133-144. 
icaKeeton,   R.   W.,   and   Koch,   F.   C:      Am.   Jour.   Physiol.,    1915,    xxxvii,   481;    also 

Popielski,  L.:     Arch.  f.  d.  ges.  Physiol.,  1901,  lxxxvi,  215. 
nMeltzer,  S.  J.:     Am.  Jour.   Physiol.,   1899,  ii,   266. 
^Cannon,  W.  B.:     Am.  Jour.  Phvsiol.,  1898,  i,  359. 

isCannon,  W.  B.,  and  Blake,  J.  B.:     Am.  Surg.,  1905,  xli,  686.     Cf.  No.  3. 
i^Macallum,  A.  B.:     See  Fitzgerald,  M.  P.,  Proc.  Roy.  Soc,  lxxxiii,  B,  56. 
i -Harvey,  B.  C.  H.,  and  Bensley,  R,  R.:     Biol.  Bull.,  Wood's  Hole,  1912,  xxiii,  225. 
"Long,  J.  H.,  et  al.:     Jour.  Am.  Chem.  Soc,  1917,  xxxix,  162  and  1493;  also  ibid., 

1916,  xxxviii,  38. 

^Jordan,  E.  V.:     Food  Poisoning,  Univ.  of  Chicago  Press,  1917. 

"Whipple,  G.  H.,  Cooke,  J.  V.,  and  Stearns,  T.:     Jour.  Exper.  Med.,  1917,  xxv,  479. 

Also  Whipple,  G-.  H.,  Stone  and  Bernheim:     Ibid.,  1913,  xvii,  286  and  307. 
JoLong,  J.  H.,  and  Fenger,  F.:     Jour.  Am.  Chem.  Soc,  1917,  xxxix,  1278. 
aoWhipple,  C.  H.,  and  Hooper,  C.  W. :     Am.  Jour.  Physiol.,  1916,  xl,  332  and  349 ;  ibid., 

1917,  xlii,  257  and  264;  Hoope:     Ibid.,  p.  280. 
aiMeltzer,  S.  J.:     Am.  Jour.  Med.  8c,  1917,  cliii,  469. 


PART  VI 
THE  EXCRETION  OF  URINE 


CHAPTER  LV1II 

THE  EXCRETION  OF  URINE 

By  R.  G.  Pearce,  B.A.,  M.D. 

It  will  be  advisable  to  introduce  the  subject  by  a  brief  review  of  the 
essential  structural  features  of  the  kidney,  in  so  far  as  they  apply  to 
the  excretory  function  of  the  organ. 

STRUCTURE  OF  THE  KIDNEY 

The  kidney  is  mainly  derived  from  the  surface  of  the  celom,  and  is  a 
mesodermal  structure.  In  this  respect  it  differs  from  ordinary  secreting 
glands,  which  are  endodermal  in  origin.  Just  as  it  is  more  or  less 
unique  in  its  development  as  a  gland,  it  is  also  unique  in  its  method 
of  functioning.  The  physiologic  theories  of  the  mechanism  of  urinary 
secretion  are  closely  related  to  the  highly  characteristic  structure  of  the 
kidney.  For  this  reason  a  brief  survey  of  the  structure  of  the  different 
parts  of  the  uriniferous  tubules  and  the  epithelial  cells  with  which  these 
are  lined,  is  advisable. 

The  uriniferous  tubule,  which  is  the  secreting  unit  of  the  kidney, 
takes  its  origin  in  the  capsule  of  Bowman,  which  may  be  likened  to  a 
hollow  sphere  of  very  delicate  epithelium,  one  side  of  which  is 
invaginated  by  a  very  much  convoluted  capillary  mass,  the  glomerulus. 
The  capsule  opens  up  by  a  narrow  twisted  neck  into  a  tubule,  which  is 
rather  tortuous  in  the  cortex  (the  proximal  convoluted  tubule),  but  soon 
takes  a  sharp  descending  course  in  the  medulla  towards  the  pelvis  of  the 
kidney,  and  doubles  back  (loop  of  Henle)  in  a  straight  course  again  to 
the  cortex,  where  it  again  makes  a  twisted  course  (the  distal  convoluted 
tubule),  and  terminates  in  a  collecting  tubule,  which,  uniting  with  other 
tubules,  collects  the  urine  and  conducts  it  to  the  pelvis  of  the  kidney. 
The  capsule  is  lined  with  very  thin  epithelial  cells,  especially  over  the 
capillaries  comprising  the  glomerulus.     The  proximal  and  distal  tubules 

507 


508 


THE    EXCRETION    OF    TRINE 


contain  epithelium  showing  a  prominent  striation.  These  striations  are 
rows  of  granules,  which  run  towards  the  lumen  of  the  cell,  becoming 
less  distinct  as  they  approach  it  and  apparently  standing  in  close  rela- 
tionship to  the  rather  prominent  internal  (lumen)  striated  border  of 
the  cell.     Some  histologists  believe  that  the  striations  at  the  border  are 


Fig.    170. — Diagram    of   the   uriniferous    tubules    (C)    the   arteries    (A),    and    the   veins    (B)    of   the 

kidney. 

really  cilia,  which  are  described  as  being  immobile.  The  cilia  are  shown 
in  Fig.  171.  The  descending  limb  of  Henle's  loop  is  lined  with  a  thin 
pavement  epithelium  with  large  bulging  nuclei.  The  distal  convoluted 
tubule  is  lined  with  cells  not  unlike  those  found  in  the  proximal  tubules, 
except  that  the  inner  border  is  not  striated.    The  diameter  of  the  lumen 


TIIK    F.XCRKTION    OF    IKIM:  509 

of  the  capsule  varies  with   the  activity  of  the  kidney,  as  is  shown  in 
the  following  figures  given  by  Brodie  and  Mackenzie.1 


RESTING 

KIDNEY  DURING 

KIDNEY 

DIURESIS 

MM. 

MM. 

Mi'iin  diameter  of  capsule 

93.4 

123.8 

"           "         "   glomerulus 

90.4 

100.0 

"           "         "   space  of  capsule 

3.0 

23.8 

Lumen  of  proximal  convoluted  tubule 

0.0 

17.6 

"        "     distal 

7.2 

20.6 

The  urinary  tubule  has  a  remarkable  Mood  supply.  The  renal  arteries 
arise  directly  from  the  abdominal  aorta  and  are  very  short.  They  run 
through  the  medulla  to  the  cortex,  and  join  with  neighboring  arteries  to 


17 


\v 


•     ■: 


Fig.    171.- — Cross  sections   of  convoluted   tubules   from   kidney   of  rat.     A,  during  slight  secretion;   B, 
during   maximal    secretion.      (From    Sauer.) 

form  arches  from  which  proceed  branches,  that  radiate  into  the  cortex 
and  give  off  smaller  branches  each  of  which  very  shortly  breaks  up  into  a 
small  capillary  tuft, — the  glomerulus,— which  lies  in  the  invaginated  sphere 
of  Bowman's  capsule.  The  capillaries  collect  into  an  efferent  vessel,  which 
appears  to  be  smaller  than  the  afferent  artery,  and  this  vessel  in  emerging 
from  the  capsule  again  breaks  up  to  form  a  capillary  network  about  the  con- 
voluted tubules,  forming  their  sole  blood  supply.  These  capillaries 
coalesce  to  form  the 'renal  vein.  The  blood  of  the  kidney  must,  accord- 
ingly, pass  through  two  sets  of  capillaries. 

The  kidney  is  richly  supplied  with  nerves,  which  are  for  the  most  part 
derived  from  the  celiac  ganglion  and  are  in  connection  with  the  splanch- 


510  THE   EXCRETION   OF   URINE 

nic  and  the  vagus.  Other  brandies  from  plexuses  in  the  region  of  the 
suprarenal  body  and  the  aorta  join  with  those  coming  from  the  celiac 
ganglion  to  form  what  is  known  as  the  renal  plexus,  which  is  arranged 
in  a  network  along  the  blood  vessels  and  on  the  walls  of  the  pelvis  of 
the  kidney.  These  fibers  are  distributed  to  the  very  smallest  blood  ves- 
sels, and  nerve  fibers  have  been  observed  among  the  eells  of  the  tubules. 

THE  MECHANISM  OF  THE  EXCRETION  OF  THE  URINE 

The  great  number  as  well  as  the  variety  of  substances  which  are  pres- 
ent in  both  the  blood  and  the  urine  makes  it  appear  improbable  that 
urine  excretion  is  dependent  upon  chemical  combinations  within  the 
renal  cells,  and  leads  us  to  seek  a  physicochcmical  mechanism  to  explain 
the  phenomenon.  Can  we  discover  the  processes  by  which  the  kidney 
fabricates  a  highly  concentrated  solution  of  salts  from  a  very  dilute 
solution  of  the  same  salts  in  the  blood  plasma?  The  problem  is  compli- 
cated by  the  fact  that  the  ratios  existing  between  the  concentration  of 
each  urinary  salt  in  the  urine  and  the  concentration  of  the  same  salt 
in  the  blood  are  different.  In  other  words,  the  urine  is  not  merely 
concentrated  blood  plasma  freed  from  protein. 

The  passage  of  water  and  salts  through  the  capillary  wall  and  through 
the  basement  membrane  surrounding  the  renal  cell  probably  takes  place 
by  simple  diffusion.  If  it  were  otherwise,  an  expenditure  of  energy 
would  be  required,  and  it  is  difficult  to  understand  how  a  basement 
membrane  could  bring  about  energy  changes.  Any  substance  to  which 
the  cell  membrane  is  permeable  will  diffuse  into  the  cell  until  an  equi- 
librium is  established  between  its  concentration  within  the  cell  and 
that  of  the  lymph  or  blood  plasma.  A  nondiffusible  substance  will  not 
enter  the  cell  because  it  can  not  pass  through  the  cell  membrane,  and 
if  it  exerts  an  osmotic  pressure,  it  will  also  tend  to  keep  the  water  in 
which  it  is  dissolved  from  entering.  If  water  does  pass  into  the  cell 
under  these  conditions,  it  is  due  to  the  expenditure  of  energy  opposed 
to  and  greater  than  that  which  is  offered  by  the  osmotic  pressure  of  the 
nondiffusible  substances.  Possible  sources  for  such  energy  are  the  pres- 
sure of  the  blood  in  the  renal  capillaries,  which  would  exert  a  force  op- 
posite to  that  of  its  osmotic  pressure,  and  the  presence  within  the  cell  of 
a  concentration  of  salts  greater  than  is  present  in  the  blood,  and  able  to 
exercise  a  sufficient  osmotic  force  to  draw  fluid  into  the  cell  against  the 
osmotic  force  of  the  nondiffusible  salts.  The  passage  of  the  urinary 
constituents  through  the  cell  might  also  be  due  to  simple  diffusion,  the 
substances  passing  through  the  cell  to  be  extruded  on  the  other  side  in 


THE    EXCRETION    OF    URINE  511 

the  same  concentration  as  m  the  blood.  In  this  case,  the  renal  cells 
would  act  merely  as  a  filter,  the  urine  having  the  same  concentration 
of  each  urinary  salt  as  is  present  in  the  blood. 

A  comparison  of  the  concentrations  of  the  urinary  salts  in  the  urine 
and  the  blood  shows,  however,  that  the  urine  is  not  merely  a  deproteiu- 
ized  blood  plasma,  so  that  other  factors  must  be  sought  to  explain  the 
excretion.  Since  the  concentration  of  the  urine  requires  the  expenditure 
of  much  more  energy  than  is  provided  by  the  known  physical  factors, 
it  is  generally  accepted  that  the  renal  cell  in  some  manner  supplies  this 
energy  by  its  metabolic  activity.  It  is  impossible  at  present  even  to 
surmise  the  nature  of  the  process.  Two  possibilities  may  be  considered. 
One  is  that  the  urine  is  a  filtrate  of  the  blood  which  has  passed  through 
a  portion  of  the  renal  epithelium  into  the  tubules  as  a  very  dilute  fluid, 
resembling  the  blood  plasma  minus  its  colloidal  substances,  and  that 
this  dilute  fluid  is  concentrated  by  the  reabsorption  of  fluid  and  of  salts 
by  other  cells  of  the  kidney,  and  again  replaced  in  the  blood  stream.  The 
other  is  that  the  salts  and  fluid  are  each  actively  and  individually  ex- 
creted by  the  kidney.  Whichever  condition  is  the  true  one,  the  fact 
remains  that  the  change  in  the  concentration  entails  the  expenditure 
of  a  great  amount  of  energy  on  the  part  of  the  renal  cells. 

The  energy  which  the  kidney  must  use  in  the  actual  work  of  concen- 
trating the  urine  from  the  fluid  of  the  blood  plasma  can  not  be  com 
puted  from  a  comparison  of  the  concentration  of  the  urinary  salts  as  a 
whole  in  both  the  blood  and  the  urine.  Each  constituent  must  be  con- 
sidered apart.  We  can  not,  for  example,  determine  the  molecular  con- 
centration of  the  blood  plasma  and  the  urine  (by  measuring  A)  (page 
10)  and  estimate  the  work  which  is  expended  in  producing  the  con- 
centration from  the  observed  difference.  On  the  basis  of  such  comparisons, 
however,  it  is  said  that  the  excretion  of  100  c.c.  of  urine  requires  at  the 
minimum  500  kilogrammeters  of  work  (Cushny2).  Even  this  conserva- 
tive estimate  may  be  wrong,  for  it  does  not  take  into  consideration  the 
possibility  that  the  excretion  of  water  by  the  kidney  requires  energy 
expenditure  on  the  part  of  the  renal  cells. 

Theories  of  Renal  Function 

For  many  years  two  rival  hypotheses  have  dominated  the  teaching  of 
the  mechanism  of  renal  function.  Bowman  and  Heidenhain  postulated 
that  the  constituents  of  the  urine  are  secreted  by  the  vital  activity  of 
the  epithelium  of  the  capsule  and  the  tubules.  The  glomerular  capsule 
secretes  the  water  and  the  easily  diffusible  salts  in  a  dilute  solution,  and 
the  uriniferous  tubules  add  to  this  fluid  the  various  organic  and  inor- 
ganic  salts   to   bring   the   urine   to   the  necessary   concentration.      This 


512  THE   EXCRETION    OF    URINE 

theory  has  been  termed  the  vital  theory.  Ludwig,  on  the  other  hand, 
advanced  what  is  termed  the  physical  theory,  which  holds  that  the 
glomerulus  and  capsule  act  simply  as  a  filter,  which  allows  the  fluid 
of  the  blood  plasma  to  pass  through  in  a  very  dilute  solution  and  in 
large  amounts.  This  fluid  is  concentrated  by  physicochemical  processes 
on  its  passage  along  the  urinary  tubules  to  the  pelvis  of  the  kidney. 

Both  of  these  theories  are  inadequate  and  fail  to  explain  the  phenom- 
ena which  research  has  shown  to  occur  in  the  kidney,  but  they  have 
served  to  develop  what  Cushny  terms  a  modem  theory  of  urinary 
excretion. 

The  Modern  Theory  of  Urine  Formation.- — This  theory  accepts  the 
general  scheme  of  filtration  and  reabsorption  of  Ludwig,  but  pays  due 
respect  to  the  fact  that  the  known  physical  forces  are  not  adequate 
to  explain  the  reabsorption  which  must  occur  in  the  tubules.  It  therefore 
supplements  Ludwig 's  theory  by  assuming  a  vital  activity  on  the  part 
of  the  epithelium  of  the  tubules  in  reabsorbing  fluids  and  salts  from 
the  dilute  filtrate  coming  from  the  glomerulus  and  capsule.  A  large 
amount  of  plasma  fluid  is  filtered  through  the  walls  of  the  glomerular 
vessels.  This  fluid  has  the  same  concentration  of  the  salts  to  which  the 
capsule  is  permeable  as  does  the  blood  plasma,  but  it  is  free  of  the  col- 
loidal substances  normally  present  in  the  plasma.  The  blood  leaving  the 
glomerulus  is  therefore  a  somewhat  concentrated  solution  of  plasma  col- 
loids, and  must  have  returned  to  it  the  proper  amount  of  water  and 
salts  to  make  it  an  optimum  fluid  for  the  body  cells.  This  is  accomplished 
by  active  absorption  from  the  glomerular  filtrate.  The  salts  that  are  of 
no  use  to  the  body  are  not  reabsorbed  and  therefore  appear  in  highly 
concentrated  form  in  the  urine.  These  salts  are  termed  nonthreshold  sub- 
stances, and  since  their  presence  in  the  plasma  is  unnecessary,  they  con- 
tinue to  be  excreted  as  long  as  they  are  present  in  any  concentration  in 
the  blood.  The  salts  that  are  necessary  for  the  plasma  are  termed 
threshold  substances,  and  are  reabsorbed  until  they  are  again  present  in 
the  plasma  in  optimal  strength.  For  example,  urea  continues  to  be  ex- 
creted as  long  as  any  is  present  in  the  blood,  while  glucose  is  completely 
reabsorbed  so  long  as  its  concentration  remains  under  a  more  or  less 
fixed  level. 

It  is  impossible  to  give  a  summary  of  the  arguments  which  have  been 
advanced  in  support  of  any  of  the  theories.  However,  since  the  modern 
theory  appears  to  offer  a  better  explanation  of  the  established  facts,  it 
may  be  wise  to  recount  some  of  the  best  experimental  evidence  in  support 
of  it. 

First,  we  must  inquire  as  to  the  amount  of  deproteinized  blood  plasma 
which  the  capsule  must  filter  off  from  the  blood  in  order  to  furnish  the 


THE    EXCRETION    OF    I  RINE  .r>l:! 

amount  of  the  various  sails  excreted  each  day  and  the  amount  of  water 
absorbed  by  the  epithelium  of  the  tubules  to  account  for  llie  concentra- 
tion in  which  the  salts  arc  found  in  the  urine.  In  order  to  produce  20 
grams  of  urea  in  1200  c.e.  of  urine.  ('»()  liters  of  blood-plasma  fluid  con- 
taining 0.03  per  cent,  of  urea  would  have  to  be  filtered  through  the  cap- 

|  '20 
sulci —    =G000),  and  5.9  liters  of  water  returned  to  the  blood  from 

)  0.03 
the  uriniferous  tubules.    Since  the  bloodflow  through  the  kidneys  is  very 
great,  at  least  500  liters  per  day,  only  about  13  per  cent  of  the  fluid  con- 
tained   in    the   blood   passing   through    the    glomerulus    would    pass    by 
filtration  through  the  capsule  of  Bowman. 

The  fact  that  such  a  large  amount  of  fluid  would  have  to  be  reab- 
sorbed from  the  uriniferous  tubules  (59  liters)  is  a  possible  a  priori 
criticism  of  the  theory,  but  Cushny  points  out  that  the  amount  each 
tubule  would  have  to  absorb  per  hour  would  be  very  small  (in  his  ex- 
periment on  a  cat  amounting  to  less  than  0.014  c.c.  per  hour). 

The  filtration  of  the  protein-free  blood  fluid  through  the  renal  capsule, 
like  that  through  any  other  membrane,  depends  on  several  factors.  (1) 
There  must  be  a  difference  in  the  pressure  between  the  blood  and  the 
urinary  filtrate.  In  the  laboratory  the  pressure  used  in  filtering  is 
usually  supplied  by  gravity,  but  in  the  case  of  the  filtration  of  the  urine 
through  the  capsule  the  force  is  furnished  by  the  pressure  of  blood  in 
the  glomerular  vessels.  (2)  The  character  of  the  filter  determines  what 
substances  shall  pass.  The  renal  capsule  is  a  membrane  normally  im- 
pervious to  the  proteins  of  the  blood,  but  pervious  to  the  other  constitu- 
ents. Under  certain  conditions  it  loses  this  character.  (3)  The  char- 
acter of  the  fluid  determines  how  readily  it  will  filter  through  the  mem- 
brane. If  the  fluid  contains  a  substance  which  can  not  pass  through  the 
filter  and  which  exerts  an  osmotic  pressure  in  opposition  to  the  filtering 
force,  the  rate  of  filtration  as  well  as  the  amount  filtered,  will  be  reduced. 
If  the  capsule  acts  as  a  filter  it  should  be  possible  to  alter  the  rate  of 
urine  excretion  by  varying  any  of  these  factors,  and  experimentally  this 
is  true.  The  factors  can  be  varied  in  several  ways.  If  the  blood  pressure 
is  raised  by  tying  off  several  of  the  branches  of  the  aorta,  the  urine  is 
appreciably  increased,  or  if  the  blood  pressure  is  decreased,  as  can  be 
done  by  compressing  the  renal  artery  by  means  of  a  screw  clamp,  the 
amount  of  urine  is  decreased.  In  the  artificially  perfused  kidney,  the 
fluid  exuding  from  the  ureter  increases  as  the  pressure  of  the  perfusion 
fluid  is  increased,  and  decreases  as  the  pressure  is  decreased.  Whether 
changes  in  the  pressure  in  the  blood  are  directly  responsible  for  variations 
in  the  rate  of  urine  excretion,  or  whether  they  act  indirectly  by  varying 
the  rate  of  the  bloodflow  in  the  kidneys,  has  been  the  subject  of  much 


514  THE    EXCRETION    OP    URINfi 

debate.  Probably  botb  factors  are  involved,  as  is  shown  by  the  follow- 
ing observations.  If  the  blood  pressure  is  increased  by  vasoconstriction 
in  the  splanchnic  area  produced  by  stimulation  of  the  splanchnic  nerves, 
the  flow  of  blood  through  the  kidney  is  decreased  and  the  excretion  of 
urine  falls.  Apparently,  secretion  can  continue  only  as  long  as  the  col- 
loids of  the  plasma  are  not  notably  increased,  for,  as  the  osmotic  pressure 
due  to  the  indiffusible  colloids  rises,  the  pressure  in  the  capillaries  is  no 
longer  able  to  oppose  it.  The  same  point  has  been  beautifully  shown  by 
Starling  and  his  pupils,  who  found  that  the  secretion  of  urine  ceases 
when  the  capillary  pressure  in  the  glomerulus  fell  below  that  exerted  by 
the  osmotic  pressure  of  the  blood  proteins,  the  critical  pressure  being 
from  30  to  40  mm.  Hg.  They  also  found  that  dilution  of  the  blood  with 
saline  solution  by  reducing  the  osmotic  pressure  of  the  proteins  in  the 
plasma,  was  accompanied  by  an  increase  in  the  rate  of  excretion;  excre- 
tion in  such  cases  being  maintained  at  a  blood  pressure  below  the  normal 
critical  pressure.  If  the  dilution  of  the  blood  was  made  with  saline  con- 
taining gelatin  or  gum  arabic,  on  the  other  hand,  the  diuretic  effect  was 
greatly  decreased,  and  any  fall  in  the  blood  pressure  was  followed  by  a 
suppression  in  the  urine  (Knowlton9).  These  experiments  evidently 
indicate  that  the  saline  produces  its  diuresis  by  diluting  the  plasma 
proteins  and  lowering  their  osmotic  pressure,  since  when  the  osmotic 
pressure  of  the  blood  is  maintained  by  the  addition  of  colloids  in  which 
this  is  present,  no  diuresis  occurs.  The  significance  of  these  facts,  in 
connection  with  the  raising  of  lowered  blood  pressure  after  hemorrhage, 
has  already  been  alluded  to  (page  139). 

This  view  is  confirmed  by  the  experiments  of  Barcroft  and  Straub,10 
who  showed  that  the  oxygen  consumption  is  often  not  appreciably 
raised  during  the  diuresis  produced  by  the  injection  of  saline.  If  the 
diuresis  produced  by  this  means  was  due  to  an  actual  increase  in  the 
work  of  the  kidney,  the  oxygen  consumption  would  have  been  increased. 

In  the  frog,  the  glomerulus  and  the  tubules  are  supplied  with  blood 
by  the  renal  artery,  as  is  the  case  in  the  mammal,  but  the  tubules  cu- 
riously enough  are  also  supplied  with  some  of  the  blood  coming  from  the 
lower  extremities  and  the  trunk  through  a  vessel  which  has  no  counter- 
part in  the  mammal — the  renal  portal  vein.  The  blood,  therefore,  which 
is  supplied  to  the  tubule  is  a  mixture  from  the  glomerulus  and  the  renal 
portal  system.  By  ligating  the  renal  vessels  it  is  possible  to  cut  off  the 
blood  supply  of  the  glomerulus  while  leaving  the  tubules  supplied  by  the 
renal  portal  vein.  Normally  the  pressure  in  the  renal  portal  system  is 
not  sufficient  to  force  blood  back  through  the  glomerular  vessels.  Liga- 
ture of  the  renal  vessels  at  once  results  in  a  suppression  of  the  urine. 

If  the  glomerular  vessels  are  perfused  with  Ringer's  solution   at   a 


THE    i:\<RF.TION    OF    URINE 


5 1 5 


pressure  equal  to  thai  found  in  the  aorta,  a  considerable  flow  of  fluid 
may  lie  secured  from  the  ureters,  hut  no  fluid  is  obtained  when  the  renal 
portal  vein  is  perfused  a1  a  pressure  equal  to  thai  normally  present  in 

this  vein.  Kountree  and  Geraghty11  found  that  phenolsulplioinplit  lialeiu 
added  to  the  perfusion  fluid  passed  through  the  renal  portal  vein,  did  not 
cause  secretion,  hut  when  urea  was  added  to  the  perfusate,  fluid  con- 
taining the  dye  was  obtained  from  the  ureter.  Unfortunately  the  pres- 
sure employed  in  these  experiments  may  have  allowed  some  fluid  to  he 
forced  backward  into  the  glomerulus,  so  thai  the  results  may  he  due  to 
filtration  through  the  capsule. 


Renal 
artery 


Malpighian 
corpuscle 


Renal-portal  vein 


Fig.    172. — Uiagram  of  blood  supply  of  Malpighian  corpuscle  and  of  convoluted   tubules  in   amphibian 

kidney.      (Redrawn    from    Cushny.) 


It  is  generally  accepted  that  the  proof  that  the  capsule  acts  as  a  filter 
is  fairly  complete.  Unfortunately  such  decisive  experimental  facts  can 
not  be  offered  to  prove  the  assumption  that  the  epithelium  of  the  tubules 
reabsorbs  the  excess  of  water  and  salts  which  are  filtered  off  through 
the  capsule.  If  the  modern  theory  of  urine  excretion  is  correct,  the  cells 
of  the  tubules  must  not  only  absorb  large  amounts  of  water,  but  they 
must  also  allow  for  "the  reentrance  into  the  blood,  either  completely  or 
partially,  of  certain  salts,  while  they  must  reject  others  entirely. 

"We  have  called  attention  above  to  the  fact  that  the  glomerular  filtrate  is 
very  different  from  the  urine  that  is  finally  passed.  The  urine  contains  a 
very  high  percentage  of  small  molecules,  and  the  proportion  in  which  they 


516  THE    EXCRETION    OF    URINE 

are  present  is  entirely  different  from  thai  in  the  blood  plasma  or  in  the 
glomerular  filtrate.  This  is  shown  in  the  following  figures,  which  give  an 
average  normal  value  for  the  urea,  uric  acid,  chlorine,  and  glucose  in  100 
c.c.  of  protein-free  blood  plasma  and  100  c.c.  of  urine.  In  the  third  col- 
umn is  given  the  change  in  concentration  which  has  occurred  in  the 
kidney. 


100  C.C.  PROTEIN- 
FREE  BLOOD 
PLASMA  CONTAINS 

100  C.C.  URINE 
CONTAINS 

CHANGE  IN 

CONCENTRATION 

IN  THE  KIDNEY 

Uroa 

Uric  Acid 
Chlorine 
Glucose 

.033 
.0022 
.41 
.1 

2. 
.05 

.6 

60 

22.7 
1.5 

Here  the  blood  plasma  fluid  contained  but  0.03?)  per  cent  of  urea,  and 
the  urine  2  per  cent.     Accordingly,  6  liters  of  glomerular  filtrate  would 

f2 
be  required  to  furnish  100  c.c.  of  urine,  I =  6000).     Six  liters  of 

I  0.33 
glomerular  filtrate  would  contain  6.6  grams  of  sugar,  0.132  grams  of 
uric  acid,  and  24.6  grams  of  chlorine.  But  100  c.c.  of  urine  contains  no 
glucose,  0.05  grams  of  uric  acid  and  0.6  grams  of  chlorine.  According 
to  the  modern  theory,  these  figures  indicate  that  during  the  passage  of  the 
urine  through  the  tubules  5900  c.c.  of  water,  6.6  grams  of  sugar,  24  grams 
of  chlorine  and  0.067  grams  of  uric  acid  would  have  to  be  absorbed  by 
the  renal  epithelium  in  the  production  of  100  c.c.  of  urine  containing 
the  concentration  given  above. 

Among  the  most  convincing  experiments  that  can  be  offered  in  sup- 
port of  the  absorption  of  fluid  and  salts  by  the  tubules,  are  those  in 
which  the  pressure  of  the  urine  in  the  tubules  is  slightly  increased  by 
partial  closure  of  the  ureter  (Cushny).  In  these  experiments  the  ureter 
of  one  kidney  is  partly  closed  with  a  clamp  and  the  excretion  obtained 
from  this  kidney  is  compared  with  that  of  the  opposite  normal  kidney. 
In  general,  obstruction  of  the  ureter  results  in  a  decrease  in  the  amounts 
of  water,  chloride  and  urea  excreted.  But,  curiously,  the  urea  content  is 
decreased  relatively  less  than  is  the  chloride  and  water  content.  These 
results  can  be  explained  on  the  basis  that  any  pressure  acting  to  oppose 
the  head  of  pressure  producing  filtration  in  the  glomerulus  will  reduce 
the  amount  of  the  glomerular  filtration,  and  accordingly  the  time  allowed 
for  the  passage  of  this  filtrate  along  the  tubules  is  increased  and  absorp- 
tion becomes  more  complete.  Since  urea  is  probably  not  absorbed  at  all 
and  chloride  is,  the  discrepancy  in  the  effects  on  the  excretion  of  urea 
and  chlorine  in  the  partially  obstructed  kidney  can  be  explained. 

When  very  large  amounts  of  water  are  taken  by  mouth,  it  often  hap- 


Till:    EXCRETION    OF    I  RINE  517 

pens  thai  the  urine  excreted  has  a  concentration  of  salts  less  than  thai 
presenl  in  the  fluid  of  the  blood.  Some  investigators  believe  that  such  a 
condition  is  possible  only  on  the  assumption  thai  water  is  actively  ex- 
creted,  but  a  more  plausible  explanation  based  on  1  lie  modern  theorj 
is  that  the  water  thai  is  absorbed  Erom  the  alimentary  tract  reaches  the 
kidney  ;is  a  dilute  saline  solution,  and  is  rapidly  filtered  off  in  a  form 
somewhat  more  dilute  than  the  optimal  solution  which  blood  plasma  must 
have  for  the  well-being  of  the  tissues.  The  tubules  reabsorb  the  amounts 
of  water  and  of  those  salts,  such  as  chlorides,  uric  acid,  and  sugar,  nec- 
essary to  restore  the  plasma  to  the  optimal  concentration,  but  do  not 
absorb  the  nonl  hreshold  substances,  such  as  urea. 

Tt  is  impossible  to  analyze  the  forces  that  arc  responsible  for  such  a 
degree  of  absorption  by  the  epithelium  of  the  tubules.  For  the  present 
we  must  classify  them,  for  want  of  a  better  term,  as  vital  forces.  The 
questions  that  await  immediate  investigation  are  whether  absorption 
actually  takes  place,  and,  if  it  does  so,  what  factors  cause  it  to  vary. 

Many  attempts  have  been  made,  by  destroying  the  capsules  or  the 
tubules  by  means  of  poisons  or  by  operation,  to  determine  directly  or 
indirectly  the  question  of  the  function  of  the  tubules. 

In  such  experiments,  however,  the  number  of  factors  involved  con- 
fuse the  issue  and  make  the  results  practically  valueless  so  far  as  de- 
termining the  normal  function  of  the  tubules.  Other  experimenters 
have  attempted  to  show  absorption  in  the  tubules  by  injecting  diffusible 
substances,  such  as  chemicals  and  dyes,  into  the  ureter  under  what  they 
deemed  sufficient  pressure  to  force  the  solution  into  the  tubules,  and  by 
an  examination  of  the  blood  or  the  tissues  to  determine  whether  or  not 
the  injected  substances  had  been  absorbed.  The  results  obtained  by 
this  method  are  not  convincing,  probably  chiefly  because  of  the  difficulty 
in  reaching  the  tubules.  Indeed,  it  is  very  questionable  Avhether  it  is 
possible  to  inject  a  substance  into  the  tubules  from  the  ureter. 

Years  ago  Ileidenhain,  the  exponent  of  the  vital  theory  of  excretion, 
believed  that  he  had  demonstrated  the  ability  of  the  renal  cells  to  ex- 
crete dye  substances  injected  intravenously.  Since  he  failed  to  find 
evidence  of  dye  excretion  in  the  capsule,  but  found  masses  of  dye  in  the 
tubules  and  stained  granules  in  the  cells  of  the  tubules,  he  concluded 
that  the  cells  of  the  tubules  had  the  power  to  excrete  the  dye,  and  from 
analogy  he  believed  that  the  tubules  must  likewise  excrete  the  water 
and  the  various  urinary  salts.  Subsequent  work,  however,  has  failed 
to  confirm  his  belief  that  the  capsule  is  not  concerned  in  the  excretion 
of  the  dye,  and  it  is  as  reasonable  to  explain  the  results  of  the  experi- 
ments with  the  dyes  by  assuming  that  the  masses  of  dye  substances 
found   in   the  tubules  and   in    the   cells   are   due   to  the  reabsorption   of 


518 


THE   EXCRETION    OF    URINE 


water  and  perhaps  of  some  of  the  dye  from  the  dilute  glomerular  filtrate, 
as  to  accept  Heidenhain's  hypothesis. 

In  the  following  table  taken  from  Cushny  the  movements  of  the  con- 
stituents of  the  plasma  may  be  followed  through  the  kidney.  The  ulti- 
mate destination  of  each  is  indicated  in  the  enclosures. 


Water 

Colloids 

Dextrose 

Uric  acid 

Sodium 

Potassium 

Chloride 

Urea 

Sulphate 


67  LITERS  PLASMA 
CONTAIN 


PER 
CENT 


92 


62  1. 


5360  srm. 


0.1 

0.002 

0.3 

0.02 

0.37 

0.03 

0.003 


67  gm. 

1.3  " 

200  " 

13.3  " 

248  " 

20  " 

1.8  " 


62  LITERS 

FILTRATE 

CONTAIN 

IN  ALL 


62  1. 

67   gm. 

1.3  " 

200  " 
13.3  " 

248   " 

20   " 

1.8  " 


61  LITERS 

REABSORBED    FLUID 

CONTAIN 


PER 
CENT 


61    1. 


0.11 

0.0013 
0.32 
0.019 
0.40 


67     gm. 
0.8    " 
196.5    " 

11.8    " 
242       " 


1    LITER    URINE 
CONTAINS 


PER 
CENT 


TOTAL 


95 


950  c.c. 


0.05 

0.35 

0.15 

0.6 

2.0 

0.18 


0.05 

gm. 

3.5 

<  < 

1.5 

1 1 

6.0 

1 1 

2.0 

1 1 

1.8 

1 1 

(From  Cushny.2) 

It  will  be  noted  that  the  dextrose  alone  is  completely  absorbed,  and 
that  the  urea  and  the  sulphate  are  not  absorbed  at  all  from  the  glom- 
erular filtrate.     The  other  salts  are  partly  absorbed. 

As  already  mentioned,  Barcroft  and  Straub  have  shown  that  the 
diuresis  which  results  from  the  injection  of  saline  into  the  blood  is  not 
accompanied  by  any  increase  in  the  oxygen  consumption  of  the  kidney. 
This  observation,  coupled  with  the  fact  that  the  total  amount  of  chloride, 
urea,  and  sulphate  which  is  excreted  during  saline  diuresis,  is  greater  than 
under  normal  conditions  indicates  that  the  excretion  of  these  salts  is 
not  due  to  any  vital  secretory  power  of  the  kidney,  but  rather  to  factors 
that  are  extrarenal  in  origin. 

The  diuresis  produced  by  adding  urea  or  sodium  sulphate  to  the  blood, 
on  the  other  hand,  is  accompanied  by  an  increase  in  the  oxygen  con- 
sumption of  the  kidney.  This  increase  can  not  be  due  to  active  elimina- 
tion of  these  salts  by  the  tubules,  the  work  of  which  requires  oxygen, 
for  no  increase  in  oxygen  consumption  accompanies  the  increased  ex- 
cretion of  the  same  salts  under  saline  diuresis.  Sulphate  and  urea  are 
nonthreshold  substances,  and  are  not  absorbed  by  the  tubules.  The 
explanation  of  the  oxygen  consumption  is  probably  that  the  osmotic 
pressure  which  these  bodies  in  the  glomerular  filtrate  exert  makes  it 
necessary  for  the  epithelium  to  oppose  a  greater  absorbing  force  to  con- 
centrate the  urine,  and  hence  a  greater  expenditure  of  energy  is  requird. 

Diuretics. — The  action  of  the  xanthine  compounds — caffeine,  theo- 
bromine and  theophylline— in  the  production  of  diuresis  is  unexplained. 


THE    EXCRETION    OF    I  BINE  519 

It  may  be  due  in  pari  to  vascular  changes  and  in  pari  to  reduction  in 
the  resistance  to  filtration  broughl  about  by  alteration  in  the  permea- 
bility of  the  capsule. 

According  to  the  modern  theory  the  polyuria  in  diabetes  is  produced 
by  the  excessive  amount  of  water  taken  and  by  the  inability  of  the 
kidney  to  concentrate  the  urine  againsl  the  osmotic  pressure  offered  by 
llic  concentrated  sugar  solution  in  the  tubules.  The  presence  of  the  hy- 
perglycemia in  an  amounl  higher  than  is  present  in  the  optimal  blood 
plasma  in  this  disease  makes  sugar  a  nonthreshold  substance,  so  to  speak, 
and  none  is  absorbed.  The  diuresis  following  the  injection  of  sugar  is 
therefore  of  the  same  type  as  that  produced  by  sulphate  and  urea.  The 
diuretic  action  of  the  digitalis  group  is  dependent  upon  its  influence  on 
the  circulatory  system.  If  the  circulation  is  already  sufficient,  digitalis 
does  not  cause  diuresis.  The  cause  of  the  diuresis  produced  by  pituitary 
extract  is  not  known.  It  may  be  owing  in  part  to  its  action  on  the-  cir- 
culation and  in  part  to  a  direct  action  on  the  kidney. 

Albuminuria. — The  plasma  proteins  ordinarily  do  not  obtain  entrance 
into  the  tubules  of  the  kidney.  In  disease  such  as  acute  nephritis  and 
cardiac  failure,  the  plasma  colloids  are  filtered  off  through  the  capsule, 
probably  because  of  some  change  that  has  occurred  in  the  permeability 
of  its  membrane  due  to  inflammation  or  asphyxia.  In  these  cases  the 
urine  is  usually  reduced  in  amount.  Probably  there  is  no  purely  glom- 
erular or  tubular  type  of  nephritis,  both  structures  sharing  in  the  dis- 
ability. While  it  can  not  be  said  that  any  of  the  so-called  renal  tests 
that  have  been  advanced  in  recent  years  are  free  from  criticism,  they 
nevertheless  have  contributed  very  useful  information.  The  fact  that 
the  kidney  of  the  chronic  nephritic  excretes  a  urine  of  more  or  less  fixed 
low  specific  gravity  would  suggest  that  here  there  is  an  impairment  of 
the  resorbing  mechanism,  and  the  failure  of  a  kidney  to  excrete  the 
proper  amount  of  dye,  as  in  the  phenolsulphonephthalein  test,  suggests 
an  impairment  in  the  filtering  apparatus.  Hard  and  fast  rules  can  not 
be  applied,  however,  and  probably  the  tests  must  at  present  be  inter- 
preted for  the  kidney  as  a  whole. 

The  Influence  of  the  Nervous  System  on  the  Secretion  of  Urine. — In 
spite  of  numerous  and  repeated  attempts  to  demonstrate  that  a  nervous 
mechanism  governs  the  excretion  of  urine,  no  proofs  which  are  above 
criticism  have  been  forthcoming.  Stimulation  of  the  splanchnic  nerves 
results  in  a  diminution  in  the  excretion  of  urine,  probably  because  of  a 
diminution  in  the  blood  supply  of  the  renal  vessels  owing  to  the  vasocon- 
striction. Stimulation  of  the  vagus  nerves  below  the  level  of  the  cardiac 
branches  has  been  said  to  result  in  the  augmentation  of  the  rate  of  urine 
excretion  (Asher  and  Pearce12).    The  results  are  doubtful,  however,  since 


520 


THE    EXCRETION    OF    URINE 


there  is  no  increase  in  the  oxygen  absorption  under  the  above  conditions 
(Pearce  and  Carter13).  In  the  light  of  the  modern  theory  this  vagal  diure- 
sis would  be  interpreted  as  due  to  an  inhibition  of  the  absorption  in  the 
tubules  rather  than  an  augmentation  in  the  actual  excretion  of  urine. 

There  is  no  doubt  that  the  renal  nerves  profoundly  affect  the  excretion 
of  urine,  but  that  they  do  so  directly  is  very  improbable,  since  perfectly 


Fig.   173. — Nerve  supply  of  the  kidney.     K,  kidney;   Si,  S->,  major  and   minor   splanchnic   nerves;    V, 
vagus;    C.G.,   Celiac   ganglion;  A,   aorta.      (From   Cushny.) 

adequate  renal  function  can  be  maintained  in  animals  that  have  had  the 
kidneys  entirely  removed  and  then  replaced.  There  are  numerous  re- 
flexes that  affect  the  rate  of  urine  excretion  by  constriction  of  the  renal 
vessels.  Injury  to  the  bladder  or  ureter,  abdominal  injuries  to  the  kid- 
ney, or  even  cold  applied  to  the  skin,  may  result  in  incomplete  suppres- 
sion of  the  urine. 


CHAPTER  LIX 

THE  AMOUNT,  COMPOSITION,  AND  CHARACTER  OF  URINE 
By  R.  G.  Pearce,  B.A.,  M.D. 

Tn  the  chapters  on  digestion  and  metabolism,  we  have  followed  the 
course  which  food  takes  with  especial  reference  to  the  nutrition  of  the 
body.  The  excretion  of  these  elements  of  nutrition  is  taken  up  under  a 
number  of  the  subdivisions  of  physiology,  viz.,  respiration,  digestion, 
kidney  function  and  the  skin.  In  the  chapters  on  digestion  attention  was 
called  to  the  fact  that  the  feces,  besides  containing  the  indigestible  resi- 
due of  the  aliment,  contain  several  excretory  products  Avhich  at  one 
time  or  another  have  actually  been  within  the  body  proper.  These  in- 
clude normally  the  pigments  of  the  body  and  many  of  the  heavier  mineral 
salts,  such  as  iron,  magnesium,  lime  and  phosphates;  and  under  abnormal 
conditions,  as  when  the  metals  are  given  as  medicine,  bismuth  and  mer- 
cury. The  respiratory  system  excretes  most  of  the  oxygen  and  carbon. 
In  this  chapter  we  shall  take  up  the  manner  in  which  the  body  rids  itself 
of  the  nitrogenous  and  some  of  the  mineral  waste  materials.  Even  at 
the  risk  of  repetition,  it  will  be  advantageous  to  recapitulate  certain  facts 
concerning  the  essential  chemical  structure  of  the  urinary  constituents, 
so  that  we  may  be  in  a  position  to  appreciate  the  kidney  function  in 
health  and  disease. 

"We  now  know  that  the  kidney  does  not  form  any  of  the  specific  con- 
stituents of  its  secretion  (except  hippuric  acid).  These  substances  are 
formed  in  the  various  tissues  of  the  body,  and  are  brought  to  the  kidneys 
by  the  blood,  Avhere  they  are  eliminated.  But  while  the  constituents  are 
unchanged  in  chemical  composition  in  the  urine  from  that  in  which  they 
are  found  in  the  blood,  they  do  occur  in  greatly  changed  proportions. 
It  is  this  variation  in  the  concentration  of  the  urinary  constituents  in 
the  blood  and  the  urine  which  presents  the  most  important  and  at  the 
same  time  the  most  difficult  question  in  the  physiology  of  the  kidney. 
In  the  following  table  the  percentage  composition  of  the  blood  plasma  is 
compared  with  that  of  an  average  sample  of  human  urine.  The  third 
column  gives  the  change  in  concentration  which  each  constituent  under- 
goes in  passing  through  the  renal  filter. 

52] 


522  THE   EXCRETION    OF    URINE 


BLOOD  PLASMA 

URINE 

CHANGE  IN 

PER  CENT 

PER  CENT 

CONCENTRATION 

Water 

no  '.»:: 

95 

— 

Proteins,   fats  and   other   colloids 

7-9 

— 

— 

Dextrose 

0.1 

— 

— 

Urea 

0.03 

2 

CO 

Uric   acid 

0.002 

0.05 

25 

Creatinine 

Ammonia 

0.001 

0.04 

40 

Sodium 

0.32 

0.35 

1 

Potassium 

0.02 

0.115 

7 

Calcium 

0.008 

0.015 

2 

Magnesium 

0.0025 

0.006 

2 

Chlorine 

0.009 

0.27 

30 

Phosphates  (PO„) 

0.003 

0.18 

60 

Sulphates   (SO,) 

Amino  acids 

The  Amount  of  Urine 

The  amount  of  urine  passed  in  twenty-four  hours  varies  with  the 
amount  of  fluid  ingested  and  the  proportion  of  fluid  retained  by  the  body 
or  excreted  by  other  channels.  Under  ordinary  conditions  a  twenty-four- 
hour  sample  amounts  to  from  1000  to  1800  c.c.  of  urine.  On  a  constant 
water  intake  the  volume  of  urine  is  extremely  variable  for  any  single 
day  or  part  of  the  day  (Addis  and  Watanabe3).  The  average  volume  of 
urine  excreted  by  twenty  individuals  on  the  third,  fourth  and  fifth  days 
of  a  constant  diet  in  which  the  fluid  intake  was  2,070  c.c.,  varied  from 
1,013  to  1,712  c.c.  for  a  twenty-four-hour  period,  from  684  to  1,195  c.c. 
for  the  first  twelve  hours  of  the  day,  and  from  501  to  788  c.c.  for  the 
first  eight  hours  of  the  day.  In  normal  subjects  the  amount  of  urine 
excreted  during  the  night  is  usually  less  than  that  during  the  day.  This 
is  such  a  constant  finding  that  in  cases  where  more  than  50  per  cent  of 
the  urine  is  excreted  in  the  twelve  hours  of  the  night,  suspicions  of  renal 
disease  should  be  aroused. 

The  Specific  Gravity  of  Urine 

In  urine  collected  at  different  times  of  the  day  the  specific  gravity  may 
show  a  variation  of  ten  points.  Indeed,  the  specific  gravity  of  the  urine 
has  been  taken  as  a  functional  test  by  clinicians.  With  a  constant  food 
and  water  intake  the  variations  found  in  the  specific  gravity  of  samples 
of  urine  taken  at  two-hour  periods  in  normal  and  pathologic  conditions 
are  very  useful  as  criteria  of  the  functional  state  of  the  kidney.  Fixa- 
tion of  the  specific  gravity  at  either  a  low  or  a  high  figure  is  not  the 
usual  normal  finding.    The  following  figures  will  illustrate: 


SlMOUNT,   COMPOSITION,   ami  character  of   urine 


523 


DAY 

NIGHT 

8-10 

A.M. 

10.12 
A.M. 

12-2 
P.M. 

2  I 

P.M. 

4-6 
P.M. 

6-8 
P.M. 

8-8 

P.M. -A.M. 

Normal    person 

In  Hypertensive  Nephritis 

In   Myocardial  Decompensation 

1.016 

1.010 
1.018 

1.019 
1.009 

1.020 

1.012 
1.010 
1.019 

1.014 
1.009 
1.018 

1.112(1 
1.019 

0.050 

1.010 
1.010 
1.021 

1.020 

1.009 

1.022 

(Compiled  from  Mosenthal's  figures.) 

The  proportion  of  water  to  total  solids  is  often  very  similar  in  plasma 
and  urine,  but  when  water  is  taken  in  large  quantities  the  urine  shows 
mueh  greater  changes  than  does  the  blood,  and  the  solids  may  sink  to  a 
very  low  concentration.  On  the  other  hand,  when  little  fluid  is  taken  or 
when  the  skin  and  bowel  eliminate  a  large  amount  of  fluid,  the  urine 
may  become  very  concentrated  without  any  change  in  the  blood  plasma. 
The  total  solids  in  urine  can  be  determined  with  approximate  accuracy 
by  multiplying  the  last  two  figures  of  the  specific  gravity  by  the  con- 
stant coefficient  0.233   (Haeser). 


The  Depression  of  Freezing-  Point 

While  the  solids  of  the  blood  consist,  for  the  most  part,  of  proteins 
and  colloids,  those  of  the  urine  are  made  up  of  inorganic  salts  and  small 
organic  molecules.  The  molecular  concentration — that  is,  the  total  number 
of  molecules  in  a  given  quantity  of  fluid — is  under  ordinary  conditions 
much  greater  in  the  urine  than  in  the  blood.  The  molecular  concentra- 
tion may  be  determined  by  the  depression  of  the  freezing  point  of  a  fluid 
below  that  of  distilled  water  (see  page  10).  Blood  freezes  almost  con- 
stantly at  -0.56°  C,  while  urine  may  freeze  at  variations  of  temperature 
between  -1°  C.  and  -2.5°  C. ;  if  very  concentrated  it  may  freeze  at  a 
temperature  as  Ioav  as  -5°  C,  or  if  dilute  the  freezing  point  may  be  as 
high  as  -0.075°  C. 

The  variability  of  the  freezing  point  and  the  specific  gravity  of  the 
urine  lead  us  to  a  consideration  of  the  relationship  of  the  urinary  volume 
to  its  concentration.  In  the  first  place,  the  volume  of  water  ingested  is 
more  frequently  than  otherwise  in  excess  of  the  minimum  absolutely  re- 
quired by  the  body,  and  is  subject  to  greater  variation  than  the  sub- 
stances excreted  in  the  urine.  The  kidney  is  able  to  eliminate  one  con- 
stituent of  the  plasma  which  may  be  present  in  excess  without  involving 
any  changes  in  others.  For  example,  when  salt  is  added  to  the  food  and 
excreted  in  the  urine,  the  total  chlorides  are  increased,  but  the  amount 
of  urine  and  the  other  constituents  may  remain  unchanged;  or,  again,  as 
may  happen,  excess  of  salt  leads  to  an  increase  in  the  volume  of  the 
urine,  but  the  salt  concentration  remains  constant  while  that  of  the 
other  urinary  bodies  is  decreased.     Similarly,  although  the  rate  of  urea 


524  THE    EXCRETION    OF    URINE 

excretion  is  not  demonstrably  augmented  by  an  increase  in  the  volume 
of  the  urine,  an  increase  in  the  rate  of  urea  excretion  induced  by  the 
ingestion  of  urea  is  accompanied  by  a  larger  volume  of  urine.  That  these 
two  factors  may  not  stand  in  a  causal  relationship  to  each  other  is  sug- 
gested by  recent  work  of  Addis  and  Watanabe,8  who  find  no  quantitative 
relationship  between  the  rate  of  increase  in  urea  excretion  and  the 
increase  in  urine  volume,  and  who  believe  that  the  apparent  relationship 
is  due  to  a  common  cause,  such  as  alteration  in  the  rate  of  circulation  or 
change  in  the  activity  of  the  kidney  cells.  Nevertheless,  there  appears  to 
be  a  limit  set  to  the  power  of  the  kidney  to  take  the  urinary  salts  or  water 
from  the  plasma  and  to  place  them  in  the  urine  in  quite  different  propor- 
tions. The  definite  amount  of  water  required  to  hold  the  urinary  salts 
has  been  termed  the  "volume  obligative"  (Ambard5).  These  limits  of 
concentration  may  be  fixed  by  the  energy  which  the  kidney  can  bring  to 
act  against  the  osmotic  resistance. 

The  inconstancy  in  the  behavior  of  the  kidney  toward  ingested  salts  is 
probably  due  to  the  fact  that  the  salts  reach  the  kidney  in  the  concen- 
tration in  which  they  are  held  by  the  blood  plasma,  and  not  as  they  were 
ingested.  Tf  salt  is  absorbed  rapidly  enough  to  disturb  the  salt  equilib- 
rium of  the  tissues  and  plasma,  then  water  Avill  be  abstracted  from  the 
tissues,  and  the  plasma  on  reaching  the  kidney  will  eliminate  the  salt 
and  water  together.  The  difference  in  the  reaction  arises  from  the 
varied  activity  in  the  tissues  in  general  rather  than  in  the  kidney  itself. 

The  Reaction  of  Urine 

In  man  and  the  carnivora  this  reaction  is  generally  acid  to  litmus  or 
phenolphthalein.  The  cause  is  found  in  the  fact  that  the  end  products 
of  protein  metabolism  give  rise  to  sulphuric  and  phosphoric  acids  the 
acidity  of  which  gives  the  urine  an  acid  reaction.  In  the  herbivorous 
animals  the  alkaline  reaction  is  due  to  the  fact  that  vegetables  and 
fruits  contain  salts  of  dibasic  or  polybasic  acids,  such  as  acid  potassium 
malate,  citrate,  acetate,  and  tartrate.  Oxidation  of  these  in  the  bod" 
gives  rise  to  carbonates.  Some  of  the  carbonic  acid  is  excreted  through 
the  lungs,  and  hence  the  associated  base,  generally  sodium  or  potassium, 
is  combined  so  as  to  form  a  weak  basic  salt. 

The  measurement  of  the  acidity  of  the  urine  in  terms  of  gram  anions 
or  cations,  like  the  same  measurement  in  blood,  requires  the  use  of  the 
rather  difficult  electrical  or  indicator  method,  the  principle  of  which  has 
been  described  in  Chapter  Y.  Expressed  in  terms  of  Ch,  the  acidity 
varies  between  4.7  xlO-7  and  100  x  10"7.  The  total  potential  acidity — 
that  is,  the  number  of  II  ions  which  will  be  formed  in  the  face  of  a  con- 


AMOUNT,    COMPOSITION,    AND    CHARACTER    OF    [TRINE  525 

tinual  neutralization  of  those  in  solution  may  be  obtained  fairly  accu 
pately  by  titrating  the  urine  with  ',u  normal  alkali  in  the  presence  <>f 
neutral  potassium  oxalate,  using  phenolphthalein  as  an  indicator  (Folin). 
The  results  maj  be  expressed  in  acidity  per  cent  in  terms  of  c.c.  N  LO 
NaOH  required  to  neutralize  LOO  c.c.  of  urine.  If  the  ammonia  excretion 
is  added  to  the  titration  results,  the  total  potential  acidity  is  very  closely 
measured. 

The  urine  is  more  alkaline  shortly  after  meals  than  at  other  times. 
since  acid  is  being  excreted  by  the  gastric  glands.  It  is  more  acid  on  a 
moat  than  on  a  vegetable  diet,  and  is  acid  during  starvation  because 
protein  is  then  the  chief  metabolite.  Tn  disease  there  is  no  characteristic 
variation,  save  thai  the  urine  is  more  generally  acid,  which  may  be  ex- 
plained by  the  fact  that  in  serious  illness  the  diet  is  restricted.  When 
the  acidity  is  increased,  the  excretion  of  ammonia  is  usually  greater, 
since  ammonium  carbonate,  the  forerunner  of  urea,  acts  as  an  alkali  and 
neutralizes  the  acid  radicles.  This  rise  in  ammonia,  however,  is  not 
always  proportional  to  the  acid  radicles  present,  since  the  fixed  alkali 
derived  from  fruits  and  vegetables  may  be  sufficient  to  neutralize  the 
acid  formed. 

THE  SOLID  CONSTITUENTS 

For  practical  reasons  we  shall  divide  the  constituents  of  the  urine  into 
normal  and  abnormal.  The  former  are  present  in  the  average  urine  in 
amounts  sufficient  to  be  detected  by  ordinary  means;  the  latter  only 
rarely  appear  in  detectable  quantities.  In  a  person  eating  an  ordinary 
diet  the  most  important  organic  and  inorganic  constituents  of  the  urine 
are  as  follows: 

Total  Solids  (40  to  GO  Grams)  in  One  Liter  or  Normal  Urine 

ORGANIC    CONSTITUENTS,    25-40    GM.  INORGANIC  CONSTITUENTS,   15-25  GM. 


Urea,  20-35  gm.  Sodium  chloride  (NaCl),  8-15  gm. 

Creatinine,  1.011.5  gm.  Phosphoric  acid  (P205),  2.5-3.5  gm. 

Uric  acid,  0.5-1.25  gm.  Sulphuric  acid,   (S03),  2-2.5  gm. 

Hippuric  acid,  0.1-1.7  gm.  Potassium  (EL.O),  2-3  gm. 

Other    constituents     (ethereal    sulphates,  Sodium   (Na20),  4-6  gm. 

oxalic  acid,  urinary  pigments,  etc.),  Calcium   (CaO),  0.1-0.3  gm. 

1.5-2.3  gm.  Magnesium   (MgO),  0.2-0.5. 

Ammonia  (NH3),  0.3-1.2  gm. 
Iron   (in  pigment),  0.001-0.040. 

(Compiled  from  Mosenthal's4  figures.) 

These  urinary  salts  are  present  in  the  blood,  and  are  excreted  only  by 
the  kidney.  An  investigation  of  the  mechanism  of  renal  secretion  must 
therefore  include  a  study  of  the  relationship  existing  between  the  con- 
centration of  the  urinary  salts  in  the  blood  and  in  the  urine. 


526  Tin:  i:xcri:tiox  of  trine 

The  Normal  Organic  Salts  of  the  Urine 

Nitrogenous  Constituents. — The  greater  number  of  the  organic  salts  of 
the  urine  are  made  up  of  bodies  which  contain  nitrogen,  and  which  are 
derived  from  the  protein  element  of  nutrition.  The  proteins,  which  form 
the  chief  building  material  of  the  body,  are  broken  up  into  their  con- 
stituent amino  acids  in  the  intestinal  tract  and  absorbed  as  such  by  the 
blood.  Portions  of  these  acids  are  taken  up  by  the  tissues  to  repair  and 
to  replace  those  proteins  which  have  been  discarded,  and  the  remaining 
protein,  in  excess'  of  the  body  need  for  amino  acids,  is  deamidized,  the 
major  portion  of  the  carbon,  oxygen  and  hydrogen  being  oxidized  to 
form  COo  and  water,  and  the  lesser  portion  of  these  elements  being  com- 
bined with  the  nitrogen  to  form  urea,  ammonia,  uric  acid,  etc.  A  similar 
fate  later  awaits  the  nitrogen  moiety  which  found  a  place  in  the  tissues, 
and  which  is  replaced  in  turn  by  new  nitrogenous  bodies.* 

Since  all  the  ingested  nitrogen,  except  a  small  and  rather  constant 
amount  which  is  lost  by  the  feces  and  the  sweat,  is  excreted  in  the  urine, 
the  total  nitrogen  of  the  urine  has  been  taken  as  a  measure  of  the  nitro- 
gen or  protein  metabolism  of  the  body.  In  normal  conditions  the  protein 
metabolism  is  adjusted  in  such  a  manner  that  the  nitrogen  intake  is 
equal  to  the  nitrogen  output,  a  condition  known  as  nitrogenous  equilib- 
rium. If  the  nitrogen  intake  is  reduced  below  the  actual  body  needs, 
the  excretion  of  nitrogen  is  greater  than  the  intake  which  indicates  that 
the  body  protein  is  replacing  the  protein  usually  furnished  by  the  food. 
The  minimum  amount  of  protein  that  the  body  must  have  to  maintain 
equilibrium  varies  in  individuals,  but  is  on  the  average  between  5  and  6 
grams  of  nitrogen  a  day,  which  corresponds  to  about  40  grams  of  pro- 
tein. With  the  ordinary  diet  it  is  usually  between  12  and  20  grams  a 
day,  or  represents  from  75  to  125  grams  of  protein.  Since  protein  is  not 
stored  by  the  body  except  in  periods  of  growth  or  after  periods  of  under- 
nutrition, an  increase  in  the  protein  food  is  accompanied  by  an  increase 
in  the  nitrogen  excreted  in  the  urine.  For  this  reason,  unless  the  amount 
of  nitrogen  ingested  is  known,  the  study  of  the  total  nitrogen  of  the  urine 
gives  no  information  concerning  the  nature  of  the  nitrogen  metabolism 
of  the  body.  The  total  output  of  nitrogen  per  day  usually  amounts  to 
10  to  15  grams — from  1  to  2  per  cent  of  the  urine  by  weight. 

All  the  nitrogenous  bodies  of  the  urine  are  normally  nonprotein,  and 
arise  from  similar  bodies  in  the  blood,  where  they  exist  in  concentra- 
tions of  from  20  to  30  mg.  per  100  c.c.  In  excreting  the  nitrogen  of  the 
urine  the  kidney  therefore  takes  it  from  a  solution  in  which  it  is  found 
in  a  concentration  of  0.03  per  cent  on  the  average  and  delivers  it  to  a 


'For  further  details  see  page  610. 


AMOINT,    COMPOSITION,     AM)    (1 1  Ali.\(  Tl  M    OF     CHINK  527 

solution  containing  an  average  of  L.00,  or  concentrates  it  at  least  30 
times. 

Urea.- Tin1  chief  of  the  nitrogenous  bodies  of  the  urine  is  urea,  the 
origin  of  which  lias  been  fully  described  in  the  chapters  on  metabolism. 
No  constituent  of  the  urine  is  subject  to  greater  variation  both  in  abso- 
lute and  in  relative  amounts.  On  an  average  diet  containing  120  grams 
of  protein  per  day,  the  absolute  urea  excretion  may  amount  to  about  30 
grams;  on  a  low  protein  diet  it  may  be  only  a  few  grams.  When  the  pro- 
tein intake  is  high,  the  nitrogen  eliminated  as  urea  may  be  90  per  cent 
of  the  total  nitrogen;  but  when  the  protein  intake  is  low,  this  proportion 
may  fall  to  (50  per  cent.  The  difference  is  because  on  a  low  protein  diet 
the  greater  percentage  of  nitrogen  eliminated  is  endogenous  in  origin, 
and  urea,  which  is  the  chief  constituent  of  the  exogenous  nitrogen  moiety 
of  the  urine,  is  accordingly  decreased  on  low  diets. 

In  recent  years  the  importance  of  the  relationship  between  the  con- 
centration of  the  urinary  constituents  in  the  blood  and  the  urine  has 
been  much  insisted  upon,  and  since  the  estimation  of  the  amount  of 
urea  in  the  blood  and  the  urine  is  relatively  simple,  most  of  the  work 
has  been  done  by  using  these  values.  Ambard  and  Weil5  believe  that  a 
quantitative  relationship  exists  between  the  rate  of  urine  excretion  and 
the  concentration  of  urea  in  the  blood  and  the  urine,  since  the  urea  in 
the  blood  acts  as  a  stimulus  to  the  renal  cells.  By  comparing  the  rate 
of  urea  excretion  and  the  concentration  of  urea  in  the  blood  and  urine 
in  a  mathematical  formula,  they  have  obtained  a  value  which  they  be- 
lieve is  more  or  less  fixed  for  the  normal  kidney.  This  expression  is 
knoAvn  as  Ambard' s  coefficient  and  formula*  and  has  been  used  as  a 
means  of  evaluating  the  functional  capacity  of  the  kidney. 

Whatever  the  value  of  the  formula  may  be  in  expressing  the  relationship 
existing  between  the  rate  of  urea  excretion  and  the  concentration  of  this 
salt  in  the  blood,  it  is  certain  that,  in  diseased  conditions  Avhere  impair- 
ment of  the  kidney  is  certain,  the  concentration  of  urea  in  the  blood  re- 
mains permanently  at  an  abnormally  high  average  level,  although  the 


'Ambard   and   Weil's   formula   is: 

Ur 

K  = ,   in   which: 


K  =  coefficient  of  urea  excretion   (Constant  of  Ambard). 

Ur  —  grams  of  urea  per  liter  of  blood. 

D  =  output  of  urea  in  grams  per  24  hours. 

P  =  weight   of  the  patient. 

C  =  grams  of  urea  per  liter  of  urine. 

70  =  standard   weight. 

25  =  standard   concentration   of  the  urine. 


The  average  value  for  this  constant  in  normal  individuals  is  said  to  lie  between   .0C  and   .09. 
Critical    reviews    of    the    work    have    been    published    recently    by    Maclean6    and    by    Addis    and 
Watanabe.3 


528  THE    EXCRETION    OF    URINE 

amount  of  urea  excreted  during  twenty-four  hours  may  be  exactly  the 
same  as  under  normal  conditions.  Probably  the  increased  concentration 
of  urea  in  the  blood  under  these  conditions  is  a  compensatory  measure 
to  provide  sufficient  pressure  to  cause  its  excretion  through  a  damaged 
outlet.  It  is  this  increase  in  urea  of  the  blood  which  is  indicated  by  the 
term  urea  retention  in  nephritis. 

It  must  not  be  lost  sight  of,  however,  that  the  approximate  constancy 
of  the  combined  formula  is  due  in  large  part  to  the  mathematical  con- 
struction, and  also  to  the  fact  that  any  increase  in  the  concentration  of 
urea  in  the  blood  is  usually  accompanied  by  an  increased  rate  of  urea 
excretion.  The  factors  which  are  most  variable  occur  as  the  square  or 
the  square  roots  of  their  values,  and  thus  the  disturbing  effect  they  pro- 
duce on  the  constancy  of  the  resultant  of  the  formula  is  greatly  re- 
duced, while  the  most  constant  factor,  the  concentration  of  urea  in  the 
blood,  is  used  with  modification.  In  such  a  complex  mechanism  as  the 
renal  function  it  is  very  probable  that  other  factors  are  of  great  im- 
portance in  controlling  the  rate  of  urinary  excretion.  Many  of  these 
factors  can  not  admit  of  mathematical  expression.  The  writer  seriously 
doubts  the  advisability  of  adopting  an  empirical  formula  as  a  means 
of  expressing  unknown  physiologic  laws.  Such  measures  are  apt  to 
give  a  sense  of  knowledge  altogether  false,  and  thus  hinder  research 
progress. 

The  upper  limit  of  blood  urea-nitrogen  is  about  20  mg.  per  100  c.c. 
which  would  correspond  to  about  0.45  gm.  of  urea  per  liter  of  blood. 
The  average  figure  is  half  of  this  amount.  The  maximum  concentration 
of  urea  in  the  urine  is  seldom  over  8  per  cent.  On  this  basis  the  kidney 
can  raise  the  concentration  of  the  urea  in  the  urine,  at  a  conservative 
estimate,  from  100  to  200  times.  Normally  the  daily  output  of  urea 
nitrogen  may  range  from  8  to  12  gm.,  and  the  nitrogen  which  it  contains 
is  roughly  80  per  cent  of  the  total  excretion  for  the  day. 

Ammonia.- — The  chief  source  of  ammonia  in  the  body  is  from  the  ni- 
trogenous portion  of  the  deamidized  amino  acids.  The  ammonia  found 
in  excess  in  the  portal  blood  is  derived  from  ingested  ammonium  salts 
and  from  ammonia  resulting  from  bacterial  action  on  proteins  in  the 
intestinal  tract.  The  ammonia  of  the  body  is  present  chiefly  in  the  form 
of  ammonium  carbonate,  and  it  is  this  salt  that  is  the  precursor  of  urea. 
Because  ammonium  carbonate  is  so  readily  converted  into  urea  by  the 
tissues  of  the  body,  little  ammonia  is  normally  present  in  the  systemic 
blood.  The  greater  portion  of  the  ammonia  that  finds  its  way  into  the 
urine  serves  as  a  base  to  transfer  acid  radicles  either  ingested  or  formed 
within  the  body.  The  amount  of  ammonia  in  the  urine,  therefore,  is  an 
indirect  measure  of  the  extent  of  urea  formation  and  of  the  acid  bodies 


\\lor\T.    COMPOSITION,     \\l>    CHARACTER    OP    [TRINE  529 

of  t  in*  blood.  For  the  latter  reason  the  determination  of  the  ammonia 
excretion  in  urine  is  of  sonic  clinical  importance.  The  ingestion  <>r 
mineral  acids  increases  the  ammonia  excretion,  while  alkalies  lend  to 
reduce  it.  During  fasting  and  in  discuses  such  as  diabetes,  where  there 
is  an  abnormal  metabolism,  the  amounl  of  ammonia  in  the  urine  is  in- 
creased. Ordinarily  the  daily  output  of  ammonia  nitrogen  does  no1 
exceed  0.5-0.6  gm.,  constituting  :'>-f>  per  cent  of  the  total  amount  of 
nitrogen. 

Creatinine. — On  a  meat-free  diet  the  daily  excretion  of  creatinine  is 
remarkably  constant,  amounting  to   from  7  to  11   mg.  per  kilogram  <d* 
body  weight.     For  this  reason   its  determination   is  accepted  as  an   in- 
dispensable   feature    in    metabolism    investigations    involving   urine    an 
alysis. 

Any  "toss  variation  from  the  normal  amount  indicates  the  certain 
failure  of  the  attendants  to  collect  all  of  the  twenty-four-hour  specimen 
of  urine.    Normally  the  blood  contains  from  1  to  2  mg.  per  100  c.c. 

The  creatinine  is  one  of  the  last  of  the  urinary  constituents  to  accumu- 
late in  the  blood  during  renal  insufficiency,  and  for  this  reason  affords 
a  reliable  prognostic  indication  concerning  the  patients'  condition.  A 
rise  in  the  creatinine  concentration  of  the  blood  is  evidence  of  serious 
renal  disease,  patients  with  concentrations  of  5  mg.  never  recovering 
•  base  and  Meyers)7  The  concentration  of  creatinine  in  the  urine  is 
about  100  times  greater  than  in  the  blood. 

Tn  adult  man  creatine  does  not  appear  in  the  urine  save  during  starva- 
tion or  wasting  diseases.  In  woman  it  is  absent  save  after  postpartum 
resolution  of  the  uterus.  Children  commonly  excrete  creatine  along 
with  creatinine  until  the  middle  years  of  childhood. 

The  Purine  Bodies  and  Uric  Acid. — The  most  important  purine  in 
human  urine  is  uric  acid.  Xanthine  is  the  next  in  importance,  and  small 
amounts  of  hypoxanthine,  guanine,  and  adenine  are  found.  Among  the 
most  interesting  of  the  salts  of  the  urine  to  the  clinician  are  the  urates, 
because  an  accumulation  of  uric  acid  in  the  body  was  believed  to  be 
responsible  for  many  obscure  clinical  conditions.  Tt  is  quite  true  that 
the  salts  of  uric  acid  are  found  in  higher  than  normal  amount  in  some 
diseases,  especially  gout,  leukemia,  and  chronic  nephritis,  but  the  many 
vague  theories  associated  with  uric  acid  and  disease  have  long  ago  been 
■exploded. 

The  human  body  has  the  almost  unique  distinction  among  mammals 
of  not  being  able  to  destroy  any  of  the  uric  acid  it  produces,  and  hence 
all  the  uric  acid  formed  during  metabolism  must  be  excreted  in  the  urine. 
Unfortunately  the  kidney  appears  to  be  less  competent  to  rid  the  body 
of  this  Avaste  than  it  is  of  the  other  urinary  metabolites,  and  one  of  the 


530  THE    EXCRETION    OF    URINE 

earliest  signs  of  renal  insufficiency  is  now  held  to  he  a  failure  of  the 
kidney  to  prevent  the  uric  acid  of  the  hlood  from  increasing.  Perhaps 
the  reason  for  the  inability  of  the  kidney  to  excrete  uric  acid  readily 
lies  in  the  fact  that  its  salts  are  among  the  least  soluble  of  those  in  the 
urine.  It  is  on  this  account  that  when  the  urine  cools,  a  red  sediment  of 
urates  containing  certain  pigments  often  separates  out. 

The  uric  acid  of  the  urine  is  possibly  derived  entirely  from  the  purine 
metabolism  of  the  body,  in  which  the  nucleins  either  of  the  body  cells  or 
of  the  exogenous  food  take  part.  It  is  decreased  during  starvation  and 
increased  by  eating  food  rich  in  nucleins,  such  as  liver  and  sweet- 
breads. 

Under  ordinary  conditions  the  excretion  of  uric  acid  amounts  to  from 
0.3  to  1.2  gm.  per  day  (0.02  to  0.10  per  cent),  the  variation  being  de- 
pendent upon  the  state  of  health,  diet,  or  personal  idiosyncrasy.  The 
blood  of  a  normal  individual  contains  on  the  average  1.8  m,2.  of  uric 
acid  per  100  c.c.  The  kidneys  are  therefore  able  to  concentrate  the 
uric  acid  in  the  urine  from  30  to  60  times  over  its  concentration  in  the 
blood  plasma. 

The  purines  found  in  coffee  and  tea  (caffeine,  etc.)  are  excreted  in 
the  urine  as  salts  not  of  uric  acid  but  of  methylated  xanthines. 

Hippuric  Acid. — This  is  a  constant  constituent  of  the  urine  of  her- 
bivorous animals,  and  is  usually  present  in  small  amounts  in  human 
urine.  The  amount  rarely  exceeds  0.7  gm.  a  day,  but  on  a  diet  rich  in 
fruits  and  vegetables  it  may  exceed  2  gm.  It  is  interesting,  since  it  is 
the  only  urinary  constituent  that  is  synthesized  by  the  renal  cells. 

Amino  acids  are  always  present  in  small  amounts  in  the  urine,  con- 
stituting, according  to  D.  D.  Van  Slyke.  about  1.5  per  cent  of  the  total 
nitrogen.  The  estimation  of  the  ammo-acid  nitrogen  of  the  urine  has 
not  been  found  to  be  of  any  clinical  significance.8 

The  aromatic  oxyacids  are  normally  present  in  the  urine  in  varying 
amounts.  These  include  phenol,  indoxyl,  skatoxyl.  and  phenylacetic, 
paraoxyphenyl,  propionic,  oxymandelic  and  homogentisic  acids.  These 
bodies  are  derived  from  phenylamino  acids,  such  as  tyrosine,  tryptophane, 
and  phenylalanine.  It  is  believed  that  the  putrefactive  decomposition 
of  proteins  in  the  large  intestine  results  in  the  production  of  these  toxic 
bodies.  The  body  protects  itself  by  oxidizing  them  and  uniting  them 
to  sulphuric  acid  to  form  the  ethereal  or  conjugated  sulphates,  which 
are  found  in  the  urine  in  the  form  of  sodium  or  potassium  salts.  The 
determination  of  the  amounts  of  these  bodies  in  the  urine  has  therefore 
been  taken  as  an  index  of  the  putrefaction  going  on  within  the  bowel. 

The  chief  of  these  bodies  is  urinary  indican,  which  is  found  usually  as 
a  potassium  salt.     The  test  for  indican  in  the  urine  consists  in  oxidiz- 


AMOUNT,    COMPOSITION,    AND    CHARACTER   OF    URINE  53] 

ing  the  indoxy]  in  an  acid  solution  by  means  of  Eerric  chloride  to  indigo 
blue,  and  shaking  ou1  the  indigo  blue  with  chloroform.  The  depth  of 
the  color  of  the  chloroform  affords  a  rough  means  of  determining 
the  amount  of  indican  present.  The  fact  thai  the  indican  test  is  nega- 
tive must  not  be  taken  to  mean  that  the  intestinal  processes  are  normal, 
for  if  the  intestine  fails  to  contain  phenylated  amino  acids,  or  the  proper 
bacteria  are  Qo1  present,  no  indican  will  be  found.  On  the  oilier  hand, 
the  putrefactive  process  of  the  large  bowel  may  not  be  very  extensive, 
yet  the  amount  of  indican  in  the  urine  be  increased,  because  of  greater 
absorption  due  to  constipation. 

Skatole,  a  fecal-smelling  substance,  is  formed  by  certain  kinds  of  bac- 
teria. The  greater  proportion  of  this  substance  is  excreted  by  the  bowel, 
but  if  the  person  is  constipated,  some  of  it  may  find  its  way  into  the 
blood  to  impart  a  fecal  odor  to  the  breath  and  urine.  Its  presence 
therefore  has  some  diagnostic  importance. 

A  very  interesting  body  which  is  sometimes  found  in  the  urine  is 
hoinogcntisic  acid.  It  is  thought  to  be  an  intermediate  step  in  the  metab- 
olism of  tyrosine,  and  is  found  in  the  urine  of  people  suffering  from 
alkaptonuria.  The  disease  is  remarkable  in  that  it  appears  to  run  in 
families  and  produces  no  ill  effects.  Homogentisic  acid  is  a  strong 
reducing  agent,  and  for  this  reason  may  be  confused  with  sugar  in 
Fehling's  test. 

The  inorganic  constituents  of  the  urine  include  the  acids:  chlorides, 
sulphates  and  phosphates;  and  the  bases:  sodium,  potassium,  magnesium, 
and  calcium. 

The  Acids  of  the  Urine. — The  chlorides  compose  the  bulk  of  the  acid 
radicles  in  the  urine.  Although  they  appear  to  be  necessary  constituents 
of  the  living  cell,  they  do  not,  so  far  as  known,  enter  into  combinations 
with  the  organic  constituents.  The  tissues  appear  to  require  a  rather 
definite  concentration  of  sodium  chloride  in  order  to  carry  on  their 
work,  for  reduction  in  the  sodium-chloride  intake  of  the  body  results 
in  a  reduction  in  the  chloride  excretion  by  the  urine.  In  salt  starvation 
the  chlorides  may  disappear  entirely  from  the  urine,  the  amount  of 
chloride  excreted  appearing  to  be  closely  related  to  the  amount  of  salt 
ingested.  When  the  intake  is  constant,  the  rate  of  excretion  is  likewise 
more  or  less  constant,  but  a  sudden  reduction  in  the  salt  of  the  diet  may 
be  accompanied  by  a  slight  decrease  in  the  salt  content  of  the  blood, 
with  an  attendant  loss  of  water.  On  the  other  hand,  when  the  salt  is 
again  taken,  there  is  a  retention  of  salt  and  of  water,  with  a  consequent 
increase  in  body  weight,  until  equilibrium  is  re-established  on  the  old 
level.  While  the  above  is  the  usual  reaction,  a  considerable  retention  of 
salt  without  an  increase  in  the  water  content  of  the  body  may  occur  in 


532  THE    EXCRETION    OP    URINE 

some  apparently  normal  cases.     This  is  due  probably  to  the  deposition 
of  salt  in  the  tissues. 

Careful  studies  fail  to  confirm  the  idea  that  there  is  a  fixed  relation- 
ship between  the  salt  and  the  water  of  the  body.  As  with  the  nitroge- 
nous constituents,  however,  there  appears  to  be  a  relationship  between 
the  rate  of  excretion  of  chlorides  and  the  amount  of  chloride  in  the  blood. 
Ambard  believes  that  this  relationship,  like  that  of  the  excretion  of  urea 
to  the  blood  urea,  is  capable  of  being  expressed  mathematically  (see 
page  527),  if  allowance  is  made  for  the  fact  that  NaCl  is  not  excreted 
after  it  falls  below  a  certain  concentration  in  the  blood  equal  to  about 
5.62  gm.  per  1000  c.c.  This  level  is  more  or  less  constant  for  normal 
individuals,  but  is  considerably  increased  in  disease  of  the  kidney.  This 
is  known  as  the  threshold  of  chloride  excretion. 

The  amount  of  sodium  chloride  excreted  in  the  urine  in  twenty-four 
hours  varies  betAveen  8  and  20  gm.  a  day,  according  to  the  intake.  It 
is  therefore  apparent  that  the  kidney  is  able  to  concentrate  the  salts 
of  the  plasma  from  ten  to  twenty  times. 

The  Sulphates. — Since  the  inorganic  sulphates  do  not  form  an  im- 
portant constituent  of  the  food,  the  greater  portion  of  the  sulphates  of 
the  urine  are  derived  from  the  sulphur  found  in  the  protein  molecule. 
For  this  reason  the  sulphates  of  the  urine,  like  the  nitrogen,  are  a  meas- 
ure of  protein  metabolism.  An  increase  in  the  nitrogen  excretion  is 
accompanied  by  an  increase  in  the  sulphur  excretion,  the  ratio  being 
about  5  to  1.  The  daily  output  of  sulphur  is  between  1  and  3  gm.  The 
greatest  output  is  in  the  form  of  the  alkaline  sulphates,  about  10  pe 
cent  in  combination  with  aromatic  bodies,  and  a  small  amount  in  com- 
bination with  amino  acids  and  neutral  organic  salts. 

The  phosphates  of  the  urine  are  derived  from  the  food  and  from  the 
oxidation  of  phosphorus-containing  bodies  in  the  tissues  such  as 
nuclein,  lecithin,  etc.  The  daily  excretion  varies  between  1  and  5  gm., 
calculated  as  P20-.  When  calcium  or  magnesium  is  present  in  the 
food,  they  are  excreted  by  the  bowel  as  phosphate,  and  proportionately 
less  is  found  in  the  urine.  The  amount  usually  excreted  in  the  feces 
equals  about  30  per  cent  of  the  total. 

Since  phosphates  in  the  urine  exist  as  a  mixture  of  the  mono-  and  di- 
sodium  hydrogen  phosphates,  they  have  an  important  bearing  on  the 
reaction  of  the  urine,  the  amount  of  each  varying  with  the  degree  of 
the  acidity  of  the  urine. 

On  a  heavy  protein  diet  the  urine  is  acid  on  account  of  the  sulphuric 
and  other  acids  formed  from  the  meat,  and  in  this  case  there  is  a  greater 
amount  of  phosphoric  acid  and  the  mono-sodium  hydrogen  phosphate. 
When  the  urine  is  alkaline  or  less  acid,  as  it  is  on  a  vegetable  diet,  there 


wioi'XT,    COMPOSITION",    A.ND   CHARACTEB   OF    I  him-:  533 

is  a  Large  amount  of  the  disodium  hydrogen  phosphate.  Since  calcium 
and  magnesium  phosphates  arc  more  soluble  than  the  diphosphates  of 

the  same  metals,  deposits  of  the  earthy  phosphates  are  often  found  in 
neutral  or  alkaline  urines.  When  the  urine  is  heated,  the  diphosphate 
of  calcium  breaks  up  into  the  mono-calcium  and  a  tri-calcium  phos- 
phate, which  accounts  for  the  fine  turbidity  often  taken  for  albumin  in 
the  flame  test.  Addition  of  acid  will  cause  this  to  disappear.  The  crys- 
tals of  triple  phosphates  which  occur  in  alkaline  urine  are  ammonium 
magnesium  phosphate,  NH4MgP04. 

KIDNEY  REFERENCES 

(Monographs) 

Beddard,  A.  P.:     Recent   Advances   in    Physiology,   Longmans.   Green   &  Co.,   London, 

1900. 
Cushny,  A.  U.:     Secretion  of  Urine,  Longmans,  Green  &  Co.,  London,  1917. 

(Original  Papers) 

iBrodio,  T.  G.,  and  Mackenzie,  J.  J.:     Proe.  Roy.  Soc,   1914,  lxxxvii,  B,  593. 

'-('uxlmv,  A.  h\:     Secretion  of  Urine,  1917,  p.  48. 

■'■Addis  and  Watanabe:     Jour.  Biol.  Chem.,  1916,  xxiv,  203. 

iMosenthal,  H.  O.:     Arch.  Int.  Med.,  1915,  xvi,  733. 

■Ainliard   and   Weil:      Physiologic   normale    et    pathologique   des   reins,   Paris,    1914, 
J.  B.  Bailliere  et  tils'. 

sMaclean,  F.  C. :     Jour.  Exper.  Med.,  1915,  xxii,  212. 

"Chase  and  Movers:     Jour.  Am.  Med.  Assn.,  1910,  lxvii,  931. 

sVan  Slyke,  D.*  D.,  and  Meyer,  G.  M.:     Jour.  Biol.  Chem.,  1912,  xii,  399;  and  1913, 
xvi,  197,  213  and  231. 

oKnowlton,  F.  P.:     Jour.  Physiol.,  1911,  xliii,  219. 
"•Parcroft,  J.,  and  Straub,  IL :      Jour.  Physiol.,  1910,  xli,  145. 
uPowntrce  and  Geraghty:     Jour.  Pharm.  and  Exper.  Therap.,  1910,  i,  579. 
i-Asher  and  Pearee,  R.  G.:     Zeitschr.  f.  Biol.,  1913,  lxiii,  83. 
i;;Pearce,  R.  G.,  and  Carter,  E.  P.:     Am.  Jour.  Physiol.,  1915,  xxxviii,  350. 


PART  VII 

METABOLISM 


CHAPTER  LX 
METABOLISM 

Introductory. — The  object  of  digestion,  as  we  have  seen,  is  to  render 
the  food  capable  of  absorption  into  the  circulatory  fluids — the  blood  and 
lymph.  The  absorbed  food  products  are  then  transported  to  the  various 
organs  and  tissues  of  the  body,  where  they  may  be  either  used  at  once 
or  stored  away  against  future  requirements.  After  being  used,  certain 
substances  are  produced  from  the  foods  as  waste  products,  and  these  pass 
back  into  the  blood  to  be  carried  to  the  organs  of  excretion,  by  which  they 
are  expelled  from  the  body.  By  comparison  of  the  amount  of  these  ex- 
cretory products  with  that  of  the  constituents  of  food,  we  can  tell  how 
much  of  the  latter  has  been  retained  in  the  body,  or  lost  from  it.  This 
constitutes  the  subject  of  general  metabolism.  On  the  other  hand,  we  may 
direct  our  attention,  not  to  the  balance  between  intake  and  output,  but  to 
the  chemical  changes  through  which  each  of  the  foodstuffs  must  pass  be- 
tween absorption  and  excretion.  This  is  the  subject  of  special  metabolism. 
In  the  one  case  we  content  ourselves  with  a.  comparison  of  the  raw  ma- 
terial acquired  and  the  finished  product  produced  by  the  animal  factory; 
in  the  other  we  seek  to  learn  something  of  the  particular  changes  to  which 
each  crude  product  is  subjected  before  it  can  be  used  for  the  purpose  of 
driving  the  machinery  of  life  or  of  repairing  the  worn-out  parts  of  the 
body. 

In  drawing  up  a  balance  sheet  of  general  metabolism,  we  must  select 
for  comparison  substances  that  are  common  to  both  intake  and  output.  In 
general  the  intake  comprises,  besides  oxygen,  the  proteins,  fafs  and  car- 
bohydrates; and  the  output,  carbon  dioxide,  water  and  the  various  nitrog- 
enous constituents  of  urine.  This  dissimilarity  in  chemical  structure  be- 
tween the  substances  ingested  and  those  excreted  limits  us.  in  balancing  the 
one  against  the  other,  to  a  comparison  of  the  smallest  fragments  into  which 
each  can  be  broken  by  chemical  agencies.  These  are  the  elements,  and  of 
them  carbon  and  nitrogen  are  the  only  ones  which  it  is  possible  to  measure 

534 


MKTAl'.OLISM  535 

with  accuracy  in  both  intake  and  output.  Prom  balance  slic»-t s  of  intake 
and  output  of  carbon  and  nitrogen  and  from  information  obtained  by  ob- 
serving the  ratio  between  the  amounts  of  oxygen  consumed  by  the  animal 
ami  of  carbonic  acid  excreted,  we  can  draw  far-reaching  conclusions  re- 
garding  the  relative  amounts  of  protein,  fat  and  carbohydrate  that  have 
been  involved  in  the  metabolism. 

As  has  already  been  stated,  the  essential  nature  of  the  metabolic  proc- 
ess in  animals  is  one  of  oxidation — that  is,  one  by  which  large  unstable 
molecules  are  broken  down  to  those  that  are  simple  and  stable.  Dur- 
ing this  process  of  catabolism,  as  it  is  called,  the  potential  energy  locked 
away  in  the  large  molecules  becomes  liberated  as  actual  or  kinetic  energy — 
that  is,  as  movement  and  heat.  It  therefore  becomes  of  importance  to 
compare  the  actual  energy  which  an  animal  expends  in  a  given  time  with 
the  energy  which  has  meanwhile  been  rendered  available  by  metabolism. 
We  shall  first  of  all  consider  this  so-called  energy  balance  and  then  pro- 
ceed  to  examine  somewhat  more  in  detail  the  material  balance  of  the  body. 

ENERGY  BALANCE 

The  unit  of  energy  is.  the  large  calorie  (written  C),  which  is  the  amount 
of  heat  required  to  raise  the  temperature  of  one  kilogram  of  water  through 
one  degree  (Centigrade)  of  temperature.*  We  can  determine  the  calorie 
value  by  allowing  a  measured  quantity  of  a  substance  to  burn  in  com- 
pressed oxygen  in  a  steel  bomb  placed  in  a  known  volume  of  water  at  a 
certain  temperature.  Whenever  combustion  is  completed,  we  find  out 
through  how  many  degrees  the  temperature  of  the  water  has  become 
raised  and  multiply  this  by  the  volume  of  water  in  liters.  Measured 
in  such  a  calorimeter,  as  this  apparatus  is  called,  it  has  been  found  that 
the  number  of  calories  liberated  by  burning  one  gram  of  each  of  the  proxi- 
mate principles  of  food  is  as  follows : 

~     ,    ,     -,     .      f  Starch    4.1 

Carbohydrate!5  \  „  .  n 

J  \  Sugar    4.0 

Protein    5.0 

Fat  9.3 

The  same  number  of  calories  will  be  liberated  at  whatever  rate  the  com- 
bustion proceeds,  provided  it  results  in  the  same  end  products.  When 
a  substance,  such  as  sugar  or  fat,  is  burned  in  the  presence  of  oxygen,  it 
yields  carbon  dioxide  and  water,  which  arc  also  the  end  products  of  the 
metabolism  of  these  foodstuffs  in  the  animal  body;  therefore,  when  a  gram 
of  sugar  or  fat  is  quickly  burned  in  a  calorimeter,  it  releases  the  same 

'The  distinction  between  a  calorie  and  a  degree  of  temperature  must  be  clearly  understood.  The 
former  expresses  quantity  of  actual  heat  energy;  the  latter  merely  tells  us  the  intensity  at  which  the 
heat   energy  is  being  given   out. 


536 


METABOLISM 


aim  unit  of  energy  as  when  it  is  slowly  oxidized  in  the  animal  body.  But 
the  ease  is  different  for  proteins,  because  these  yield  less  completely  oxi- 
dized end  products  in  the  animal  body  than  they  yield  when  burned  in 
oxygen;  so  that,  to  ascertain  the  physiologic  energy  value  of  protein,  we 
must  deduct  from  its  physical  heat  value  the  physical  heat  value  of  the 
incompletely  oxidized  end  products  of  its  metabolism.  It  is  obvious  that 
we  can  compute  the  total  available  energy  of  our  diet  by  multiplying  the 
quantity  of  each  foodstuff  by  its  calorie  value. 

Methods. — In  order  to  measure  the  enersrv  that  is  actuallv  liberated 


Fig.  174. — Respiration  calorimeter  of  the  Russell  Sage  Institute  of  Pathology,  Eellevue  Hospital, 
New  York.  At  the  right  is  seen  the  table  with  the  absorption  tubes;  and  in  the  middle,  at  the 
back,  the  electric  control  table  for  regulating  the  temperature  of  the  double  walls  of  the  calorimeter. 
At   the   extreme  left   is   the   oxygen  cylinder.      (Lusk's   Science'   of  Nutrition.) 

in  the  animal  body,  we  must  also  use  a  calorimeter,  but  of  somewhat  dif- 
ferent construction  from  that  used  by  the  chemist,  for  we  have  to  provide 
for  long-continued  observations  and  for  an  uninterrupted  supply  of  oxy- 
gen to  the  animal.  Animal  calorimeters  are  also  usually  provided  with 
means  for  the  measurement  of  the  amounts  of  carbon  dioxide  (and  water) 
discharged  and  of  oxygen  absorbed  by  the  animal  during  the  observation. 
Such  respiration  calorimeters  have  been  made  for  all  sorts  of  animals,  the 
most  perfect  for  use  on  man  having  been  constructed  in  America  (see  Fig. 
174).     As  illustrating  the  extreme  accuracy  of  even  the  largest  of  these, 


METABOLISM  537 

it  is  interesting  to  note  thai  the  actual  heal  given  ou1  when  ;i  definite 
amounl  of  alcohol  or  ether  is  burned  in  one  of  them  exactly  corresponds 
to  the  amount  as  measured  by  the  smaller  bomb-calorimeter.    All  of  the 

energy  liberated  in  the  body  does  not,  however,  take  the  form  of  heat.  A 
variable  amounl  appears  as  mechanical  work,  so  that  to  measure  in  calories 

all  of  the  energy  that  an  animal  expends,  i  ne  must  add  1u  the  actual  cal- 
ories given  out,  the  calorie  equivalent  of  the  muscular  work  which  has 
been  performed  by  the  animal  during  the  period  of  observation.  This  can 
be  measured  by  means  of  an  ergometer,  a  calorie  corresponding  to  425 
kilogram*  meters  of  work.  That  it  has  been  possible  to  strike  an  accurate 
balance  between  the  intake  and  the  output  of  energy  of  the  animal  body, 
is  one  of  the  achievements  of  modern  experimental  biology.  It  can  be 
done  in  the  case  of  the  human  animal ;  thus,  a  man  doing  work  on  a  bicycle 
ergometer  in  the  Benedict  calorimeter  gave  out  as  actual  heat  4,833  C, 
and  did  work  equalling  602  C,  giving  a  total  of  5,435  C.  By  drawing  up 
a  balance  sheet  of  his  intake  and  output  of  food  material  during  this 
period,  it  was  found  that  the  man  had  consumed  an  amount  capable  of 
yielding  5,459  C,  which  may  be  considered  as  exactly  balancing  the  actual 
output. 

It  would  be  out  of  place  to  give  a  full  description  of  the  respiration 
calorimeter  here.  The  general  construction  will  be  seen  from  the  accom- 
panying figure  of  the  form  of  apparatus  in  use  for  patients  in  the  Russell 
Sage  Institute.  New  York.  One  of  the  most  interesting  details  of  its  con- 
struction concerns  the  means  taken  to  prevent  any  loss  of  heat  from  the 
calorimeter  to  the  surrounding  air.  This  is  accomplished  in  the  following 
way:  The  innermost  layer  of  the  wall  is  of  copper;  then,  separated  from 
this  by  an  air  space,  is  another  wall  of  copper,  outside  of  which  are  two 
•wooden  walls  separated  from  each  other  and  from  the  outer  copper  walls 
by  air  spaces.  The  two  copper  walls  are  connected  through  thermoelectric 
couples,  so  that  an  electric  current  is  set  up  whenever  there  is  any  differ- 
ence in  their  temperatures.  The  current  is  observed  by  means  of  a  gal- 
vanometer placed  outside  the  calorimeter,  and  from  its  movements  the  ob- 
server either  heats  up  or  cools  down  the  outer  copper  walls  so  as  to  cor- 
rect the  difference  of  temperature  causing  the  current.  This  is  done  by  an 
electric  heating  device  or  by  cold  water  tubes  placed  between  the  outer- 
most copper  and  the  innermost  wooden  walls.  Since  the  temperature  of 
the  two  copper  walls  is  the  same,  there  can  be  no  exchange  of  heat  between 
them,  and  consequently  none  of  the  heat  that  is  absorbed  by  the  inner  cop- 
per walls  is  allowed  to  be  carried  away.  All  the  heat  given  out  by  the 
animal  is  absorbed  by  the  stream  of  cold  water  flowing  through  the  coils 


*A  kilogram    meter   is   the  product   of  the   load   in   kilograms   multiplied   by   the  distance   in   meters 
through  which   it  is  lifted. 


538  METABOLISM 

of  pipe  iii  the  chamber.  The  heat  used  to  vaporize  the  moisture  from 
skin  and  lungs  must  of  course  also  be  measured.  This  is  done  by  collect- 
ing the  water  vapor  in  a  sulphuric-acid  bottle  placed  in  the  ventilat- 
ing current.  By  multiplying  the  grams  of  water  by  the  factor  for  the 
latent  heat  of  vaporization,  we  obtain  the  calories  of  heat  so  eliminated. 

''The  calorimeter  contains  a  comfortable  bed  and  is  provided  with  two 
windows,  a  shelf,  a  telephone,  a  fan,  a  light,  and  a  Bowles  stethoscope  for 
counting  the  pulse.  The  ordinary  experiment  takes  about  as  long  as  a  trip 
from  New  York  to  New  London.  Patients,  as  a  rule,  doze  from  time  to 
time  or  else  try  to  work  out  some  scheme  by  which  they  can  amuse  them- 
selves without  moving.  After  three  or  four  hours  they  are  rather  bored 
by  the  quiet,  and  the  observations  are  not  prolonged  beyond  this  time. 
They  are  allowed  to  turn  over  in  bed  once  or  twice  an  hour,  but  reading 
and  telephoning  are  discouraged,  since  these  increase  the  metabolism. 
The  air  in  the  box  is  fresh  and  pure,  the  patient  suffers  no  discomfort,  and 
objections  to  the  procedure  are  very  infrequent.  Most  of  the  patients 
are  only  too  glad  of  the  extra  attention,  and  they  insist  that  the  calor- 
imeter has  a  marked  therapeutic  value."     (Du  Bois.) 

Normal  Values. — Having  thus  satisfied  ourselves  as  to  the  extreme 
accuracy  of  the  method  for  measuring  energy  output,  we  shall  now  con- 
sider some  of  the  conditions  that  control  it.  To  study  these  we  must  first 
of  all  determine  the  hasal  lieat  production — that  is,  the  smallest  energy 
output  that  is  compatible  with  health.  This  is  ascertained  by  allowing  a 
man  to  sleep  in  the  calorimeter  and  then  measuring  his  calorie  output 
while  he  is  still  resting  in  bed  in  the  morning,  fifteen  hours  after  the  last 
meal.  When  the  results  thus  obtained  on  a  number  of  individuals  are 
calculated  so  as  to  represent  the  calorie  output  per  kilogram  of  body  weight 
in  each  case,  it  will  be  found  that  1  C.  per  kilo  per  hour  is  discharged 
— that  is  to  say,  the  total  energy  expenditure  in  24  hours  in  a  man  of  70 
kilos,  which  is  a  good  average  weight,  will  be  70  X  24  =  1,680  C. 

When  food  is  taken  the  heat  production  rises,  the  increase  over  the 
basal  heat  production  amounting  for  an  ordinary  diet  to  about  10  per 
cent.  Besides  being  the  ultimate  source  of  all  the  body  heat,  food  is  there- 
fore a  direct  stimulant  of  heat  production.  This  specific  dynamic  action, 
.is  it  is  called,  is  not,  however,  the  same  for  all  groups  of  foodstuffs,  being 
greatest  for  proteins  and  least  for  carbohydrates.  Thus,  if  a  starving 
animal  kept  at  33°  C.  is  given  protein  with  a  calorie  value  which  is  equal 
to  the  calorie  output  during  starvation,  the  calorie  output  will  increase  by. 
30  per  cent,  whereas  with  carbohydrates  it  will  increase  by  only  6  per 
cent.  Evidently,  then,  protein  liberates  much  free  heat  during  its  as- 
similation in  the  animal  body;  it  burns  with  a  hotter  flame  than  fats  or 
carbohydrates,  although  before  it  is  completely  burned  it  may  not  yield 


METABOLISM  539 

bo  much  energy  as  is  the  ease,  Eor  example,  when  Eats  are  burned.  This 
peculiar  property  of  proteins  accounts  Eor  their  well-known  heating  qual- 
ities. It  explains  why  protein  composes  so  large  a  proportion  of  the  diet  of 
peoples  living  in  cold  regions,  and  why  it  is  cut  down  in  the  diet  of  those 
who  dwell  near  the  tropics.  I  ndividuals  maintained  on  a  low  protein  diet 
may  suffer  intensely  Erom  cold. 

If  we  add  to  the  basal  heat  production  of  1,680  C.  another  168  ( '.  (or 
10  per  cent)  on  account  of  food,  the  total  1,848  C.  nevertheless  falls  far 
short  of  that  which  we  know  must  be  liberated  when  wo  calculate  the 
available  energy  of  the  diet,  which  we  may  take  as  2,500  C.  What  be- 
comes of  the  extra  fuel?  The  answer  is  that  it  is  used  for  muscular  work. 
Thus  it  has  been  found  that  if  the  observed,  person,  instead  of  lying  down 
in  the  calorimeter,  is  made  to  sit  in  a  chair,  the  heat  production  is  raised 
by  8  per  cent,  or  if  he  perforins  such  movements  as  would  be  necessary  for 
ordinary  work  (writing  at  a  desk)  it  may  rise  29  per  cent — that  is  to  say, 
to  90  ('.  per  hour.  There  is,  however,  practically  no  difference  in  the  en- 
ergy output  of  a  person  lying  flat  or  lying  in  a  semi-reclining  posi- 
tion, as  in  a  steamer  chair.  Allowing  eight  hours  for  sleep  and  sixteen 
hours  for  work,  we  can  account  for  about  2,168  C,  the  remaining  300  odd 
( !.  that  are  required  to  bring  the  total  to  that  which  we  know,  from  statis- 
tical tables  of  the  diets  of  such  workers,  to  be  the  actual  daily  expenditure, 
being  due  to  the  exercise  of  walking.  If  the  exercise  is  more  strenuous, 
still  more  calories  will  be  expended ;  thus,  to  ascend  a  hill  of  1,650  feet  at 
the  rate  of  2.7  miles  an  hour  requires  407  extra  calorics.  Field  workers 
may  expend,  in  24  hours,  almost  twice  as  many  calories  as  those  engaged 
in  sedentary  occupations. 

Standard  for  Comparison 

When  the  energy  output  per  kilo  body  weight  is  determined  in  animals 
of  varying  size,  the  values  are  greater  the  lighter  the  animal.  This  is 
evident  from  the  following  results  obtained  on  dogs : 

lit  a!  production  in  calorics 
per  kilo  per  day 
35.68 
46.2 
65.16 
66.07 
88.07 

(Rubner) 

When,  on  the  other  hand,  instead  of  body  weight,  the  area  of  the  sur- 
face of  the  body  is  taken  as  the  basis  of  calculation,  results  that  are  almost 
constant  are  obtained.  Following  are  the  results  in  the  above  animals  on 
this  basis: 


Weigh\ 

!  of  dog 

(1) 

31.2 

(2) 

1S.2 

(3) 

9.6 

(±) 

0.5 

(5) 

3.19 

540 


METABOLISM 


Surface  in  square  cm. 

(1)  10,750 

(2)  7,662 

(3)  5,286 

(4)  3,724 

(5)  2,423 


Heat  production  in  calories 
l"  r  square  meter  of  sur- 
face per  day 
1036 
1097 
1183 
1153 
1212 

(Rubner) 


Such  results  have  prompted  observers  to  conclude  that  the  determining 
factor  in  the  calorie  output  of  warm-blooded  animals  is  the  relative  sur- 
face of  the  animal.  This  is  greater  the  smaller  the  animal,  with  the  con- 
sequence that  heat  is  more  rapidly  lost  to  the  surrounding  air  from  the 
surface,  thus  requiring  more  active  combustion.  Until  quite  recently  it  has 
been  generally  believed  that  such  a  relationship  between  body  surface  and 
heat  production  did  actually  exist,  but,  thanks  to  the  work  of  F.  G.  Bene- 
dict7 and  E.  F.  and  D.  Du  Bois6,  it  is  now  known  that  the  calculations  were 


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WEIGHT-KILOGRAMS 


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180 

170 

160 

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120 

110 

100 
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Fig.  175. — Chart  for  determining  surface  area  of  man  in  square  meters  from  weight  in  kilo- 
grams (Wt.)  and  height  in  centimeters  (Ht.)  according  to  the  formula:  Area  (Sq.  Cm.)  =  Wt. 
0.425   XHt.   0.725   X71.84.      (From  Dubois  and   Dubois,  Arch.   Int.   Med.,   1917,  vol.    17.) 

based  upon  incorrect  computations  of  the  body  surface.  In  the  older  re- 
searches the  calculation  was  made  by  using  a  formula  known  as  Meeh's,  in 
which  Aveight  was  multiplied  by  a  certain  factor  (viz.,  12.312  x  ^weight). 
Du  Bois,  however,  has  shown  that  an  average  error  of  16  per  cent  is  in- 
curred in  using  this  formula.  For  accurate  measurement  the  body  was 
covered  with  thin  underwear,  which  was  then  impregnated  with  melted 
paraffin  and  reinforced  with  paper  strips  to  prevent  it  from  changing  in 
area  when  removed.  This  model  of  the  surface  was  afterwards  cut  up 
into  flat  pieces  and  photographed  on  paper  of  uniform  thickness,  the  pat- 


METABOLISM  541 

terns  being  then  eul  nut,  and  weighed.     Prom  the  results  it  was  easy  to 

calculate  the  actual  surface  area. 

Where  the  height  and  weight  are  known,  a  fairly  accurate  computation 
id'  the  surface  can  he  secured  by  using  the  following  formulas:  A=AY 
XH°-7LV,X71.84;  A  being  the  surface  area  in  square  centimeters;  //  the 
height  in  centimeters;  and  W,  the  weight  in  kilograms.  Based  on  this 
formula,  a  chart  has  been  plotted  from  which  the  surface  area  may  he  de- 
termined at  a  glance  (Fig.  175).  Another  method  recently  employed  by 
Benedict  is  based  on  measurements  made  from  photographs  of  the  subject 
in  various  poses. 

By  the  use  of  these  more  accurate  measurements  of  body  surface,  it  is 
now  known  that,  although  the  surface-area  law  gives  us  constant  results 
for  the  energy  output  of  different  individuals  of  similar  build,  and  offers 
us  a  much  more  accurate  basis  for  comparing  those  of  different  laboratory 
animals,  yet  it  breaks  down  when  applied  to  men  in  widely  differing  states 
of  body  nutrition.  Thus,  in  the  case  of  a  man  who  starved  for  a  month, 
the  calorie  output  per  square  meter  of  surface  decreased  towards  the  end 
of  the  fast  by  28  per  cent.  Obviously,  therefore,  it  would  be  incorrect  to 
draw  conclusions  regarding  possible  changes  in  energy  output  of  a  series  of 
emaciated  or  corpulent  individuals  by  comparison  of  their  calorie  output 
per  square  meter  of  surface  with  that  of  normal  individuals, 

The  determining  factor  of  energy  output  is  undoubtedly  the  general 
condition  of  bodily  nutrition — the  active  mass  of  protoplasm  of  the  body 
(Benedict).  That  there  is  a  relationship  between  the  body  surface  and 
metabolism  is  undoubted,  but  the  relationship  is  not  a  causal  one.  At 
present,  therefore,  the  only  safe  method  to  employ  in  comparing  the 
metabolism  of  normal  and  diseased  individuals  is  that  called  by  Benedict 
"the  group  method,"  in  which  the  metabolism  of  groups  of  persons  of 
like  height  and  weight  is  compared,  it  being  assumed  that  such  individuals 
have  the  same  general  growth  relations.  For  the  application  of  this  group 
method,  however,  more  extensive  data  will  be  required  than  exist  at  pres- 
ent, and  although  some  of  the  conclusions  drawn  from  results  computed  on 
the  surface-area  basis  may  have  to  be  revised,  it  is  probable  that  they 
are  in  general  correct. 

Influence  of  Age  and  Sex 

The  energy  output  is  low  in  the  newly  born ;  it  increases  rapidly  during 
the  first  year,  reaching  a  maximum  at  about  three  to  six  years  of  age,  and 
then  rapidly  declining  to  about  twenty,  after  which  it  declines  much  more 
slowly.  The  decline  in  the  earlier  years  does  not  proceed  steadily,  how- 
ever, for  at  the  period  just  preceding  the  onset  of  puberty  a  decided  in- 
crease becomes  evident,  indicating  that  at  this  period  the  metabolism  of 


542  METABOLISM 

the  growing  organism  is  being  stimulated.  Females  have  a  lower  energy 
output  than  males,  and  the  stimulating  influence  of  puberty  is  less  marked 
in  them. 

In  round  numbers,  40  C.  per  square  meter  of  surface  per  hour  is  the 
energy  output  of  normal  men,  a  15  per  cent  deviation  being  considered 
as  decidedly  abnormal.  The  average  metabolism  of  fat  and  thin  subjects  is 
the  same,  but  that  of  women  is  6.8  per  cent  lower  than  that  of  men.  The 
basal  metabolism  of  a  group  of  men  and  women  between  the  ages  of  forty 
and  fifty  was  4.3  per  cent  be^w  the  average  for  the  larger  group  between 
the  ages  of  twenty  and  fifty ;  and  that  of  a  group  between  fifty  and  sixty 
years  was  11.3  per  cent  lower. 

Influence  of  Diseases 

The  measurements  have  been  made  by  the  direct  method  which  has  just 
been  described,  but  since  the  much  simpler  indirect  method  (page  554) 
yields  comparable  results,  it  is  being  adopted  for  clinical  purposes.  These 
results  were  obtained  by  making  parallel  determinations  of  energy  out- 
put by  both  methods,  in  disease  as  well  as  in  health.  Some  of  the  ob- 
servations that  have  been  made  on  the  energy  output  in  various  diseases 
are  as  follows :  In  very  severe  cases  of  exophthalmic  goiter,  heat  produc- 
tion may  be  increased  by  75  per  cent  over  the  normal;  in  severe  cases,  by 
50  per  cent.  The  warmth  of  the  skin  and  the  sweating,  which  are  promi- 
nent symptoms  of  this  disease,  are  therefore  accounted  for  by  the  in- 
creased elimination  of  heat,  and  it  is  considered  possible  that  the  other 
symptoms  would  be  produced  in  any  normal  individual  were  his  metabo- 
lism maintained  for  months  or  years  at  the  high  level  which  it  occupies  in 
goiter.  In  the  opposite  condition  of  myxedema,  the  energy  output  is 
markedly  reduced,  but  rises  slowly  during  treatment  with  thyroid  extract, 
or  much  more  rapidly  with  the  very  active  thyroid  hormone  recently  iso- 
lated by  Kendall.  In  diabetes  it  has  often  been  thought  that  the  rapid 
emaciation  and  loss  of  strength  were  dependent  upon  an  excited  state  of 
metabolism,  or  a  useless  burning  up  of  the  energy  material.  The  most 
recent  work,  however,  clearly  shows  that  this  is  not  the  case,  the  basal 
metabolism  as  calculated  pei-  unit  of  body  surface  being  within  the  limits 
indicated  above.  During  the  starvation  treatment  the  ene^gv  output  may 
be  much  below  the  normal.  In  uncompensated  cases  of  card>nrenal  r7>'.s- 
p-ase,  there  is  inereased  energy  output.  In  pernicious  anemia  the  metabo- 
lism is  normal,  although  in  revere  cases  there  may  be  an  increased  demand 
for  oxygen. 

Even  at  the  risk  of  repetition,  it  is  important  to  point  out  that  in  all 
these  diseases  the  energy  output  is  the  same  whether  measured  directly  or 
by  the  indirect  method  about  to  be  described. 


MKTAHOLIKM 


r>M 


THE  MATERIAL  BALANCE  OF  THE  BODY 

We  must  distinguish  between  the  balances  of  the  organic  and  the  in- 
organic foodstuffs.  From  a  study  of  the  former  we  shall  gain  information 
regarding  the  sources  of  the  energy  production  whose  behavior  under 
various  conditions  we  have  just  studied.  From  a  study  of  the  inorganic 
balance,  although  we  shall  learn  nothing  regarding  energy  exchange — 
for  such  substances  can  yield  no  energy — we  shall  become  acquainted 
with  several  facts  of  extreme  importance  in  the  maintenance  of  nutrition 
and  growth. 

To  draw  up  a  balance  sheet  of  organic  intake  and  output  requires  an 
accurate  chemical  analysis  of  the  food  and  of  the  excreta  (urine  and  ex- 
pired air). 

Methods  for  Measuring'  Output 

The  principle  by  which  the  output  is  measured  will  be  understood  by 
referring  to  Fig.  17G,  from  which  it  will  be  seen  that  the  calorimeter 
is  connected  with  a  closed  system  of  tubes  provided  with  an  air-tight  ro- 


<Q  j      water  to  absorb    heat  *•*-} 


I 

y.    Chamber  for  animal        /* 


Fig.  176. — Diagram  of  Atwater-Benedict  respiration  calorimeter.  As  the  animal  uses  up  the  Oe, 
the  total  volume  of  air  shrinks.  This  shrinkage  is  indicated  by  the  meter,  and  a  corresponding 
amount  of  02  is  delivered  from  the  weighed  02-cylinder.  The  increase  in  weight  of  bottles 
II  and   III   gives   the   C02;   that   of   I,   the  water  vapor. 

tary  blower  or  pump  to  maintain  a  constant  current  of  air,  as  indicated  by 
the  arrows.  Following  the  air  stream  as  it  leaves  the  chamber,  we  note 
a  side  tube  connecting  with  a  meter  to  indicate  changes  in  volume  of  the 


544  METABOLISM 

air  in  the  system.  Beyond  this  and  the  pump  is  a  specially  constructed 
bottle  containing  concentrated  II2S().„  then  one  containing  soda  lime,  and 
lastly  another  H2S04  bottle.  The  first  H2S04  bottle  absorbs  all  the  water 
vapor  contained  in  the  air  coming  from  the  chamber;  the  soda  lime  bottle 
absorbs  the  C02,  and  the  second  H2S04  bottle  absorbs  water  that  is  pro- 
duced in  the  chemical  reaction  involved  in  the  absorption  of  the  C02  by 
the  soda  lime  (2NaOH  +  C02=H20+Na2C()::).  By  weighing  these  ab- 
sorption bottles  before  and  after  an  animal  has  been  for  some  time  in  the 
chamber,  the  weight  of  H20  and  of  C02  given  out  can  be  determined.  An- 
other side  tube  leads  to  an  oxygen  cylinder,  the  valve  of  which  is  manip- 
ulated so  as  to  cause  oxygen  to  be  discharged  into  the  system  at  such  a 
rate  as  to  compensate  exactly  for  that  used  up  by  the  animal,  as  indicated 
by  the  behavior  of  the  meter.  The  amount  of  oxygen  required  is  de- 
termined either  by  weighing  the  oxygen  cylinder  before  and  after  the  ob- 
servation or  by  measuring  the  volume  of  oxygen  used  by  passing  it  through 
a  carefully  calibrated  and  very  sensitive  water  meter  inserted  on  the  side 
tube  that  connects  the  <  )2  cylinder  with  the  main  tubing  of  the  system. 
Since  muscular  activity  causes  pronounced  changes  in  the  rate  of  me- 
tabolism, means  are  usually  taken  to  secure  graphic  records  of  any  move- 
ments made  during  the  observation. 

The  growing  importance  in  clinical  investigations  of  measurements  of 
the  respiratory  exchange  and  the  necessity  for  having  methods  that  are  as 
simple  as  is  consistent  with  accuracy,  have  led  to  the  introduction  of 
several  other  forms  of  apparatus,  of  which  those  of  F.  G.  Benedict  and  of 
Tissot*  are  the  most  important.  In  the  former  a  tightly  fitting  mask, 
applied  over  the  nose  and  mouth  is  connected,  by  a  short  T-piece,  with 
the  same  tubing  as  that  used  in  the  respiration  calorimeter.  The  patient 
thus  breathes  in  and  out  of  the  air  stream  that  is  passing  along  the  tubing 
without  any  of  the  obstruction  experienced  when  the  breathing  has  to  be 
performed  through  valves,  as  in  the  older  (Zuntz)  forms  of  portable 
respiratory  apparatus.  It  is  particularly  for  studies  on  man  that  this 
apparatus  has  been  devised.  The  Tissot  and  Douglas  methods  are  shown 
in  Figs.  179  and  180.* 

To  complete  the  investigation,  it  is  necessary  that  the  urine  and  feces 
be  collected  and  the  nitrogen  excretion  measured.  When  the  respiratory 
excreta  are  measured  over  a  considerable  period  of  time,  as  in  the  large 
calorimeter,  the  urine  is  collected  for  the  same  period,  but  when  shorter 
respiratory  measurements  are  made,  the  urine  of  the  twenty-four  hours 
is  usually  taken. 

Principles  Involved  in  Calculating  the  Results. — Provided  with  the  an- 
alyses furnished  by  the  above  methods,  we  proceed  to  ascertain  the  total 


*The  Tissot   method   will   be   found   described   in   full   elsewhere    (page   554). 


METABOLISM  545 

amounts  oi*  nitrogen  and  carbon  excreted  and  to  calculate  from  the 
known  composition  of  protein  how  much  protein  must  have  undergone 
metabolism.  We  then  compute  how  much  carbon  this  quantity  of  pro- 
tein would  account  for,  and  we  deduct  this  from  the  total  carbon  excre- 
tion. The  remainder  of  carbon  must  have  come  from  the  metabolism  of 
fats  and  carbohydrates,  and  although  we  can  not  tell  exactly  which,  yet 
we  can  arrive  at  a  close  approximation  by  observing  the  respiratory  quo- 
tient (R.  Q.),  which  is  the  ratio  of  the  volume  of  carbon  dioxide  exhaled 

to  that  of  oxygen  retained  by  the  body  in  a  given  time,  i.  e.,        2   .    By  ob- 

serving  this  quotient,  therefore,  we  can  approximately  determine  the 
source  from  which  the  nonprotein  carbon-excretion  is  derived. 

Having  in  the  above  manner  computed  how  much  of  each  of  the  proxi- 
mate principles  has  undergone  metabolism,  wre  next  proceed  to  compare 
intake  and  output  with  a  viewr  to  finding  whether  there  is  an  equilibrium 
between  the  two,  or  whether  retention  or  loss  is  occurring. 

It  may  serve  to  make  clear  the  methods  by  which  these  calculations  are 
made  to  study  the  following  example: 

Example  of  a  Metaholism  Investigation. — It  is  desired  to  know  whether  a  diet  con- 
taining 125  grams  protein,  50  grams  fat,  and  500  grams  carbohydrate  is  sufficient  for  a 
man  doing  a  moderate  amount  of  work. 


Protein, 

Carbohydrate, 

Fat, 

Total, 


In  urine, 
In  feces, 
In  the  breath, 

Total, 

7/<  tained  in  Body. — 30  gm.  carbon  and  2.5  gm.  nitrogen.  This  amount  of  nitrogen  repre- 
sents 2.5x6.25  =  15.6  gm.  protein  or  75  gm.  muscle.  Now,  this  amount  of  protein  will 
account  for  8.25  gm.  carbon;  so  that  30-8.25  =  21.75  gm.  carbon  represents  21.75  x 
1.3  =  28.3  gm.  fat.  On  this  diet,  therefore,  the  subject  retains  in  his  tissues  15.6  gm. 
protein  and  28.3  gm.  fat  per  diem. 

Furnished  with  these  data  we  may  now  proceed  to  compute  how  much 
energy  must  have  been  liberated  in  the  body. 

To  express  the  above  result  in  terms  of  energy  liberated,  we  know  that 
3027.5  C.  were  supplied  and  that  all  these  have  been  used  except  15.6  X 
4.1=64  retained  as  protein,  and  28.3x9-3=263.2  retained  as  fat;  or  in 
toto  327.2  C.  We  find,  therefore,  that  3027.5  -  327.2  =  2,700  C.  have  been 
required. 


Intake 

Carbon 
62  gm. 
200 
38 

Nitrogen 
20  gm. 

Calories 
512.5 

2050.0 
465.0 

300  gm. 

20  gm. 

3027.5 

Output 

Carbon 
11  gm. 
5 
254 

(16 

.5x0.67) 

Nitrogen 
16.5  gm. 
1.0 

270  gm. 

17.5  gm. 

546  METABOLISM 

This  is  called  the  method  of  indirect  calorimetry,  and  it  has  been  clearly 
established  by  numerous  observations  that  the  results  agree  exactly  with 
those  secured  by  the  method  of  direct  calorimetry  described  above.  For 
most  purposes  the  indirect  method  is  quite  satisfactory,  and  it  is  espe- 
cially valuable  in  cases  in  which  there  are  considerable  and  sudden 
changes  in  body  temperature.  That  the  results  by  the  two  methods  should 
agree  shows  clearly  that  the  law  of  the  conservation  of  energy  must  apply 
in  the  animal  body,  for  it  is  evident  that  if  any  energy  were  derived  from 
outside  the  body  other  than  that  taken  with  the  food,  the  results  by  the 
direct  method  would  be  higher  than  those  by  the  indirect. 


CHAPTEB  LXI 

THE  CARBON  BALANCE 

Before  proceeding  to  discuss  the  special  metabolism  of  proteins,  fats 
and  carbohydrates,  it  will  be  advantageous  to  consider  briefly  some  gen- 
eral facts  concerning  the  excretion  of  carbon  dioxide  and  the  intake  of 
oxygen.  In  the  first  place,  it  is  important  to  note  that  the  extent  of  the 
combustion  process  in  the  animal  body  is  proportional  to  the  amount  of 
oxygen  absorbed  and  of  carbon  dioxide  produced,  whereas  the  nature  of 
the  combustion  is  indicated  by  the  ratio  existing  between  the  amounts  of 
carbon  dioxide  expired  and  of  oxygen  retained  in  the  body.  An  investi- 
gation of  the  carbon  balance,  in  other  words,  is  partly  quantitative  and 
partly  qualitative — quantitative  in  the  sense  that  it  indicates  how  in- 
tensely the  body  furnaces  are  burning,  and  qualitative  in  the  sense  that 
it  tells  us  what  sort  of  material  is  being  burned  at  the  time. 

THE  RESPIRATORY  QUOTIENT 

Influence  of  Diet. — The  respiratory  quotient  is  determined  by  com- 
parison of  the  volume  of  carbon  dioxide  expired  with  the  volume  of  oxy- 
gen meanwhile  retained  in  the  body  or,  as  a  formula. 

Vol.  CO,  expired 
Vol.      0,  retained 
For  the  sake  of  brevity  the  respiratory  quotient  is  often  written  R.  Q.    That 
it  serves  as  an  indicator  of  the  kind  of  combustion  occurring  will  be  evi- 
dent from  the  following  equations: 

1.  Carbohydrate:   <~\H,jOt.,  +  602=6C02  +  6HX> 

(Dextrose'.) 

e  O,  6 

2.  Fat:  C„HB(CISHMO2)i-l-80O2  =  57COJ  :  52H.O 

(Olein.) 

.-.  R.Q.=  -^-=41=0.71 

*  02  80 

3.  Protein  :  I  \  JT, ,X1S0J3  +  7702  =  63C02  +  38H,0  +  9CO(NH:,V.  +  S03 

|  Empirical  formula  for 
albumin  (Lieberkiihn).] 

HO    '63 

.-.  R.Q.—   -u°--—  —  =n.82 

*  02         77 

547 


548  METABOLISM 

4.  Conversion  of  fat  into  carbohydrate  : 

2q,HB  (CI8HM0.)  3  +  640.  =  16Ct;H].,00  +  18C0.,  +  SH20 
(Olein.) 

CO  18 

.-.  R.Q.=        '  —  —  —0.281 
^  02         (54 

5.  Conversion  of  carbohydrate  into  a  mixed  fat: 

13C0H12O6  =  C55H104O0  +  23C02  +  26H20. 
( Olcosteai  opalmit  in. ) 

Taking  carbohydrates  first,  the  general  formula  may  be  written  CH20, 
from  which  it  is  plain  that,  to  oxidize  the  molecule,  oxygen  will  be  re- 
quired to  combine  with  the  carbon  alone,  according  to  the  equation, 
CH20  +  02  =  C02  +  H20.  In  other  words,  the  volume  of  carbon  dioxide  pro- 
duced by  the  combustion  will  be  exactly  equal  to  the  volume  of  oxygen 
used  in  this  process,  in  obedience  to  the  well-known  gas  law  that  equi- 
molecular  quantities  of  different  gases  occupy  the  same  volume.  The 
respiratory  quotient  is  therefore  unity  (Equation  1).  With  fats  and  pro- 
teins, however,  the  general  formula  must  be  written  CH2-)-0,  indicating 
therefore  that  for  its  complete  oxidation  the  molecule  must  be  supplied 
with  oxygen  in  sufficient  amount  to  combine  not  only  with  all  of  the  car- 
bon, but  also  with  some  of  the  hydrogen,  forming  water;  so  that  the  vol- 
ume of  C02  produced  will  be  less  than  the  volume  of  oxygen  retained, 
and  the  respiratory  quotient  will  be  less  than  unity.  As  a  matter  of  fact, 
as  the  above  equations  show  (2  and  3),  the  respiratory  quotient  for  fats 
and  proteins  lies  somewhere  between  0.7  and  0.8,  being  usually  nearer 
0.7  in  the  case  of  fats,  and  nearer  to  0.8  in  the  case  of  proteins. 

That  the  conditions  hypothecated  in  the  equations  exist  in  the  animal 
body  during  the  combustion  of  the  foodstuffs  can  easily  be  shown  by  ob- 
serving the  respiratory  quotient  of  animals  on  different  diets.  An  her- 
bivorous animal,  suc'h  as  a  rabbit,  when  it  is  well  fed  gives  invariably  a 
respiratory  quotient  of  about  1,  whereas  a  strictly  carnivorous  animal, 
such  as  the  cat,  gives  a  respiratory  quotient  of  about  0.7.  Even  more 
striking  perhaps  is  the  comparison  of  the  respiratory  quotients  in  an 
herbivorous  animal  while  it  is  well  fed  and  after  it  has  been  starved  for  a 
day  or  two.  In  the  latter  case  the  respiratory  quotient  will  fall  to  a  low 
level  because,  by  starvation,  the  animal  has  been  compelled  to  change  its 
combustion  material  from  the  carbohydrate  of  its  food  to  the  protein  and 
fat  of  its  own  tissues. 

As  already  explained  (page  545),  it  is  from  the  respiratory  quotient 
that  Ave  are  enabled  to  tell  what  proportions  of  fat  and  carbohydrate, 
respectively,  are  undergoing  metabolism.  A  useful  table  showing  the 
percentage  of  calories  produced  by  each  of  these  foodstuffs,  after  allow- 
ing for  protein,  is  given  by  Graham  Lusk  (see  page  565). 


THE   OABBON    BALANCE  549 

Influence  of  Metabolism. — Apart  from  diet,  the  respiratory  quotient 
may  often  be  altered  by  changes  in  the  metabolic  habits  of  the  animal. 
These  arc  most  conspicuously  exhibited  in  the  case  of  hibernating 
animals.  In  the  autumn  months,  when  the  animal  is  eating  voraciously 
of  all  kinds  of  carbohydrate  food  and  depositing  large  quantities  of 
adipose  tissue  in  his  body,  the  respiratory  quotient  may  be  considerably 
greater  than  unity,  indicating  therefore  either  that  relatively  more 
carbon  dioxide  is  being  discharged  or  less  oxygen  retained.  As  a  matter 
of  fact,  it  can  easily  be  shown  that  it  is  the  former  of  the  causes  that 
is  responsible  for  the  higher  quotient,  the  explanation  for  the  increased 
production  of  C02  being  that,  as  the  carbohydrate  changes  into  fat,  the 
relative  excess  of  carbon  in  the  former  is  got  rid  of  as  C02,  as  indicated 
in  Equation  5.  On  the  other  band,  if  the  animal  is  examined  while  in 
his  winter  sleep,  it  will  be  found  that  the  respiratory  quotient  is  noiv 
extremely  low,  often  not  more  than  0.3  to  0.4,  which  may  be  interpreted 
as  indicating  either  an  excessive  absorption  of  oxygen  or  a  markedly 
decreased  excretion  of  carbon  dioxide.  As  a  matter  of  fact,  there  is  a 
great  diminution  in  both  the  excretion  of  carbon  dioxide  and  the  intake 
of  02,  because  the  whole  metabolic  activity  of  the  animal  is  extremely 
depressed,  but  this  diminution  affects  the  oxygen  to  a  much  less  degree, 
indicating  therefore  a  relative  increase  in  the  oxygen  retention.  The 
explanation  is  that  the  oxygen  is  being  used  in  the  chemical  process  in- 
volved in  the  conversion  of  the  fat  back  into  carbohydrate. 

Whatever  may  be  the  relationship  between  fat  and  carbohydrate  in 
the  nonhibernating  animal,  there  is  no  doubt  that  during  hiberna- 
tion, before  the  fat  stores  are  burned,  fat  is  converted  into  something 
closely  related  to  carbohydrates,  the  equation  for  the  process  being  rep- 
resented as  given  above  (No.  4). 

In  man  and  the  higher  mammalia,  the  only  condition  apart  from  diet 
which  can  affect  the  nature  of  the  combustion  process  is  disease;  thus 
in  total  diabetes  (page  678)  the  organism  loses  the  power  of  burning 
carbohydrate,  so  that  whatever  the  diet  may  be,  the  respiratory  quotient 
is  very  low,  never  higher  than  that  representing  combustion  of  fat  and 
protein.  It  has  been  claimed  by  certain  investigators  that  in  diabetes 
the  respiratory  quotient  may  fall  considerably  below  0.7,  indicating,  as 
in  hibernating  animals,  that  fat  is  being  converted  into  carbohydrate. 
The  most  recent  and  carefully  controlled  observations,  however,  deny 
this  claim,  and  for  the  present  we  must  assume  that  in  the  body  of  man 
fat  is  not  converted  into  carbohydrate  (see  page  G64).  In  numerous  other 
diseases  investigated  by  Du  Bois  and  others0  no  qualitative  change  in 
the  combustion  processes  in  man  has  been  brought  to  light. 


i50 


METABOLISM 


THE  MAGNITUDE  OF  THE  RESPIRATORY  EXCHANGE 

It  is  evident  that  the  amount  of  carbon  dioxide  expired  and  of  oxy- 
gen retained  will  be  proportional  to  the  energy  liberation  in  the  animal 
body.  Even  at  the  risk  of  repetition  it  should  lie  noted  that  the 
energy  exchange  can  be  very  accurately  calculated  from  the  result  of 
the  material  balance  sheet — indirect  calorimetry,  as  it  is  called  (page 
562).  On  account  of  the  comparative  simplicity  of  measuring  the  carbon 
dioxide  output  and  oxygen  intake,  it  is  natural  that  many  of  the  obser- 
vations that  have  been  made  on  energy  production  in  the  animal  body 
depend  on  the  use  of  this  method,  justification  for  which  is  found  in  the 
complete  agreement  between  the  results  of  direct  and  indirect  calorim- 
etry in  a  great  variety  of  diseases  and  conditions  in  man  (Du  Bois6).* 

In  the  first  place,  it  is  interesting  to  compare  the  respiratory  ex- 
changes of  different  animals  computed  per  kilo  body  weight.  This  is 
shown  in  the  following  table. 


OXYGEN  AB- 

CARBON   DIOXIDE 

WEIGHT 

SORBED  PER  KILO 

DISCHARGED 

VOL.    COj 

TEMPERA- 

ANIMAL 

GM. 

AND  HOUR 

PER    KILO 



TURE  OF 

GM. 

AND  HOUR 
GM. 

VOL.     O, 

AIR 

Insccta 

Field  cricket 

0.25 

• — — 

2.305 



— 

.1  mphibia 

Edible  frog 

0.06:; 
(44.2  c.e.) 

0.060 
(30.76  c.c.) 

0.69 

15°-19° 

0.105 

0.1134 

0.78 

— 

(73.4  c.c.) 

(57.7  c.c.) 

Aves 

Common  hen 

1280 

1.058 
(740  c.c.) 

1.327 

(675  c.c.) 

0.91 

19° 

Pigeon 

232-380 



3.236 

—  ■ 

— 

Sparrow 

on 

9.505 
(6710  c.c.) 

10.492 
(5334.5  c.c.) 

0.79 

18° 

Ma  in  dkiI in 

Ox 

63S,000 
660,000 



0.389-0.485 

~ 

Sheep 

66,000 

0.400 
(343  c.c.) 

0.671 
(341  c.c.) 

0.99 

16° 

Dog 

6213 

1 .303 

(011  c.c.) 

1.325 
(674  c.c.) 

0.74 

15° 

Cat 

2464 

1.356 

1.397 

0.75 

"O..J 

3047 

(047  c.c.) 

(710  c.c.) 

; } 

0.645 

(450  c.c.) 

0.766 

(3S9  c.c.) 

0.S6 

29.6° 

RaM.it 

1433 

1.012 

1.354 

0.97 

18°-20° 

Guinea  pig 

444.!) 

1.478 

1.758 

0.86 

22° 

Rat  (white) 

80.5 



3.51  S 
(1789  c.  c.) 

7° 

Mouse    ' ' 

25 



8.4 

— 

17° 

Man 

66,70 

0.292 

0.327 

— 

— 

(Modified  from  Pembrey.)17 

*For    the   convenience    of    those    who    may    desire    to   know    more    about    the    methods    of    analysis 
that  are  suitable  in   the  clinic,  a   chapter   on  the   subject   will  be   found   beginning   on   page   554. 


THE   CABBON    BALANCE  551 

Several  factors  operate  to  explain  these  differences,  and  of  ihese  the 
following  are  of  importance: 

1.  The  Body  Temperature.  -Increase  in  body  temperature  entails  in- 
creased combustion.  This  explains  why  the  metabolism  of  a  bird  is 
greater  than  that  of  a  mammal  of  the  same  size,  for,  as  is  well  known,  the 
temperature  of  a  bird  is  two  or  three  degrees  centigrade  above  that  of 
other  animals.  Rise  in  body  temperature  also  explains,  in  part  at  least, 
the  increased  metabolism  observed  in  fever. 

2.  The  Temperature  of  the  Environment. — In  considering  this  we  must 
distinguish  between  the  effect  produced  on  warm-blooded  and  on  cold- 
blooded animals.  Since  the  body  temperature  of  a  cold-blooded  animal 
is  only  one  or  two  degrees  Centigrade  above  that  of  its  environment,  it 
follows  that  the  metabolic  activity  will  be  directly  proportional  to  the 
temperature  of  the  latter.  In  a  warm-blooded  animal,  on  the  other  hand, 
the  body  temperature  remains  constant  whatever  changes  may  occur 
in  that  of  the  environment,  this  constancy  of  body  temperature  being 
dependent  on  the  fact  that  the  intensity  of  the  combustion  processes  is 
inversely  proportional  to  the  cooling  effect  of  the  atmosphere.  Thus, 
suppose  the  external  temperature  should  fall,  then  the  loss  of  heat  from 
the  body  will  tend  to  become  greater,  and  to  maintain  the  body  tempera- 
ture at  a  constant  level,  the  body  furnaces  must  burn  more  briskly,  with 
the  result  that  an  increased  excretion  of  carbon  dioxide  and  intake  of 
oxygen  will  occur. 

This  influence  of  the  surrounding  atmosphere  on  the  metabolic  activ- 
ity of  warm-blooded  animals  has,  as  already  pointed  out,  been  used  by 
several  investigators  to  explain  the  greater  combustion  per  kilo  body 
weight  of  small  as  compared  Avith  large  animals.  The  argument  is  that, 
since  the  surface  of  small  animals  relatively  to  their  mass  is  much  greater 
than  in  large  animals,  the  cooling  of  the  small  animals  will  be  proportion- 
ately greater.  The  relationship  between  surface  and  mass  is  shown  by  tak- 
ing two  cubes  and  putting  them  together;  the  mass  of  the  two  cubes  is 
equal  to  double  that  of  either  cube,  whereas  the  surface  is  less  than 
double,  since  two  aspects  of  the  cubes  have  been  brought  together.  To 
prove  the  contention,  the  respiratory  exchange  has  been  computed  per 
square  meter  of  surface  instead  of  per  kilo  body  weight,  with  the  result 
that  a  very  close  correspondence  in  the  metabolism  of  different  animals 
has  been  observed;  but  this  question  has  already  been  discussed,  and  Ave 
noAV  knoAv  that  the  law  of  cooling  can  not  be  the  only  one  that  determines 
extent  of  the  respiratory  exchange   (see  page  ~>41 ) . 

3.  Muscular  Exercise. — This  has  a  most  important  influence  on  the  ex- 
change  and  it  is  particularly  in  connection  with  it  that  studies  in  carbon- 
dioxide*  output  and  oxygen  intake  have  been  of  great  practical  value,  par- 


552 


METABOLISM 


ticularly  when  the  investigations  are  undertaken  on  men  doing  ordinary 

types  of  muscular  exercise,  such  as  walking  or  climbing.  It  is  true 
that  the  influence  of  muscular  exercise  on  the  energy  metabolism  may 
also  be  studied  by. having  a  person  in  the  calorimeter  do  exercises  on  an 
ergometer,  but  the  results  thus  obtained  are  in  many  "ways  not  nearly  so 
valuable  as  those  which  can  be  secured  by  observing  the  respiratory 
exchange  of  persons  doing  ordinary  types  of  muscular  exercise  in  the 
open.  The  following  table  of  observations  on  horses  is  of  interest  in  this 
connection. 


CONDITION 

AIR  EXPIRED 

CARBON  DIOiXIDE 

OXYGEN  ABSORBED 

co2 

IN  LITERS 

DISCHARGED  IN 

IN  LITERS  PER 

02 

PER  MINUTE 

LITERS  PER 
MINUTE 

MINUTE 

Rest 

44 

1.478 

1.601 

0.92 

Walk 

177 

4.342 

4.766 

0.90 

Trot 

3.°>.°> 

7.516 

8.093 

0.93 

It  will  be  observed  that  the  metabolism  increases  extraordinarily  for 
even  a  moderate  degree  of  work,  but  that  at  the  same  time  the  respiratory 
quotient  remains  constant.  Prom  observations  on  the  respiratory  ex- 
change of  working  men  and  animals,  extremely  important  facts  concern- 
ing the  efficiency  of  muscular  work  have  been  secured.  The  form  of 
respiratory  apparatus  (Zuntz  or  Douglas)  employed  for  this  purpose 
must  be  capable  of  being  strapped  on  the  man's  back  without  causing 
any  embarrassment  to  his  bodily  movements.  By  a  comparison  of  the 
respiratory  exchange  with  the  amount  of  work  done,  the  efficiency  of  the 
work  can  readily  be  determined.  It  has  been  found,  for  example,  that 
the  efficiency  is  much  greater  after  the  man  or  animal  has  got  into  the 
swing  of  the  work,  his  energy  expenditure  per  unit  of  work  being  much 
greater  during  the  first  half  hour's  work  in  the  morning  than  it  is 
later  on.  This  indicates  that  after  a  little  practice  the  muscles  can  ex- 
ecute a  given  movement  and  perform  a  given  amount  of  work  much 
more  smoothly  than  when  they  are  not  in  training.  Another  interesting 
outcome  of  the  investigations  has  been  to  show  that  work  done  under  ab- 
normal conditions  that  tend  to  produce  any  kind  of  muscular  strain  is 
done  inefficiently.  It  has  been  found  in  marching  soldiers,  for  example, 
that  the  slightest  abrasion  of  the  foot  greatly  increases  the  energy 
expenditure,  for  the  man,  in  trying  to  avoid  the  pain  produced  by  the 
abrasion,  brings  into  operation  muscular  groups  that  are  really  not 
required  for  the  efficient  performance  of  the  movement,  but  are  used 
instead  to  avoid  pressure  on  the  sore.  Fatigue  also  causes  inefficient 
performance  of  work;  that  is  to  say,  the  fatigued  person,  on  attempting 


THE   CARBON    BALANCE  553 

the  same  amount   of  work  as  he  performed  before  becoming  fatigued, 
will  do  so  at  a  much  greater  expenditure  of  energy. 

There  is  a  diurnal  variation  in  the  respiratory  exchange,  which  is  in 
genera]  parallel  with  the  body  temperature;  it  rises  during  the  day,  the 
time  of  activity  and  work,  and  falls  during  the  night,  the  time  of  rest 
and  sleep.  Food  also  affects  respiratory  exchange,  but  it  will  be  unnec- 
essary to  go  into  this  further  after  what  lias  been  said  on  page  5-1-7. 


CHAPTEK  I, XII* 

A   CLINICAL  METHOD  FOR  DETERMINING  THE  RESPIRATORY 

EXCHANGE  IN  MAN 

By  R.  G.  Pearce,  B.A.,  M.D. 

Principle. — Since  the  determination  of  the  respiratory  exchange  in 
man  is  of  some  importance  in  the  study  of  certain  diseases  of  the  respira- 
tion, circulation  and  metabolism,  and  also  because  directions  for  carry- 
ing out  the  necessary  procedures  are  not  generally  available,  we  have 
thought  it  might  be  of  assistance  to  include  here  brief  directions  for  the 
Tissot  and  the  Douglas  methods.  These  methods  have  been  found  to 
compare  favorably  in  accuracy  with  others  in  use  at  present,!  and  be- 
cause of  their  adaptability  and  simplicity  they  are  specially  suited  for 
clinical  work. 

By  these  methods  the  energy  metabolism  of  the  body  is  calculated  from 
oxygen  consumption  or  carbon  dioxide  excretion  per  minute  (indirect 
calorimetry)  (page  546),  the  figures  for  which  are  determined  from  the 
volume  and  percentile  gaseous  composition  of  the  expired  air. 

The  subject  breathes  through  valves  which  automatically  partition  the 
inspired  and  expired  air.  The  expirations  from  a  number  of  respirations 
are  collected  in  a  spirometer  or  bag,  and  the  volume  of  the  respirations 
per  minute  is  determined.  The  gaseous  composition  of  the  expired  air 
is  determined  by  gas  analysis,  and  the  oxygen  consumption  and  energy 
output  of  the  body  are  calculated  from  the  data  obtained. 

Description  and  Use  of  Parts  of  the  Apparatus:  1.  The  Mouthpiece 
and  Valves. — The  mouthpiece  is  made  of  soft  pure  gum  rubber,  and  con- 
sists of  an  elliptical  rubber  flange  having  a  hole  in  the  center  2  cm.  in 
diameter,  to  which  on  one  side  a  short  rubber  tube  is  attached.  On  the 
opposite  side  of  the  hole,  at  right  angles  to  the  rubber  flange,  are  at- 
tached two  rubber  lugs.  The  rubber  flange  is  placed  between  the  lips, 
and  the  lugs  are  held  by  the  teeth.  The  rubber  tube  of  the  mouthpiece  is 
connected  to  the  tube  carrying  the  valves.  The  nose  must  be  tightly 
closed  if  mouth  breathing  is  used.  This  is  accomplished  by  a  nose  clip, 
which  consists  of  a  V-shaped  metal  spring,  the  ends  of  which  are  pro- 
vided with  felt  pads.     A  toothed  rachet  is  attached  to  the  ends  of  the 


*This  chapter  is  added  for  the  convenience  of  workers  in  this  subject. 
tCarpenter:     Carnegie  Institution  of  Washington  Reports,  No.  216,   1915. 

554 


MKTIIOD    KOK    I'l  ti.k.mimni;    Kl  !S|  -|  K.\T(  )HY     EXCHANGE    IN     MAN 


555 


spring,  and  serves  to  hold  the  spring  tightly  clamped  on  the  nostrils  in 

the  proper  position  (see  Fig.  177). 

Some  individuals  experience  great  distress  when  made  to  breathe 
through  the  mouth.  For  these  it  is  best  to  use  a  face  mask.  Unfortu- 
nately at  the  present  time  no  mask  is  entirely  satisfactory.  Perhaps  the 
best  is  one  sold  by  Siebe,  Gorman  &  Co.,*  which  is  pictured  in  the  cut. 


Fig.    177. — A,   Nose  clip;   B,   Face  mask;    C,   Mouth  piece. 

After  being  placed  in  position  the  face  mask  should  be  tested  for  leaks, 
which  can  be  done  by  putting  soap  around  the  edges. 

2.  The  Valves. — The  valves  of  Tissot  are  probably  the  best  for  the 
purpose,  but  they  are  expensive  and  difficult  to  obtain.  We  have  made 
perfectly  satisfactory  valves  from  the  prepared  casings  used  in  the 
manufacture  of  bologna  sausage.  These  can  be  obtained  preserved  in 
salt,  and  they  will  keep  indefinitely  on  ice.    When  needed  a  short  piece 


"This  mask  has  been  used  extensively  by  Carpenter.     The  agent  in  this  country  is  II.   N.   Elmer, 
1140  Monadnock   Bldg.,   Chicago. 


556  METABOLISM 

is  taken,  -washed  free  from  salt  by  allowing  water  from  the  tap  to  run 
through  it,  and  softened  in  a  weak  glycerine  solution.  The  gut  becomes 
very  soft  and  pliable,  and  does  not  dry  quickly.  A  piece  of  the  casing 
about  10  cm.  long  is  threaded  through  a  glass  tube  of  about  15  mm.  bore 
and  4  to  6  cm.  long.  One  end  of  the  casing  is  brought  around  the  outside 
of  the  tubing  and  secured  by  means  of  a  thread.  The  lower  end  of  the 
membrane  is  pinched  off  and  the  casing  is  then  cut  a  little  more  than 
half  way  across  its  middle,  so  that  the  opening  will  lie  just  within  the 
free  end  of  the  tube  when  the  casing  is  drawn  back  through  it.  The 
loose  end  of  the  casing  is  slightly  twisted — an  essential  procedure — and 
is  then  secured  by  a  thread  on  the  outer  side  of  the  tube.  If  properly 
made,  the  valve  will  work  freely  without  vibration,  and  the  opening  be 
sufficiently  large  to  allow  a  good  current  of  air  to  pass.  It  should  col- 
lapse instantly  and  be  air-tight  when  the  current  of  air  is  reversed.  The 
back  lash,  or  lag  of  closure,  of  these  valves  is  extremely  small,  and 
they  will  open  or  close  with  a  pressure  of  air  not  exceeding  the  pressure 


Fig.    17S. — Diagram    of   respiratory   valves. 

changes  in  normal  respiration.  When  not  in  use,  the  valves  should  be 
kept  in  glycerine  water  on  ice.  Valves  prepared  in  this  way  have  been 
in  use  a  month  without  loss  of  efficiency.  They  are,  however,  made  with 
so  great  ease  that  new  valves  are  provided  for  each  subject,  and  they  are 
therefore  especially  adapted  to  ward  work  (Fig.  178). 

The  valves  are  inserted  in  reverse  order  into  a  supporting  metal 
T-piece,  and  the  joints  made  air-tight  by  tape.  The  stem  of  the  T  is 
connected  with  the  mouthpiece.  Through  a  rubber  tube  of  about  3/4 
inch  bore,  the  expired  air  is  collected  in  the  spirometer,  or  Douglas  Bag. 

3.  The  Tissot  Spirometer  is  pictured  in  Fig.  179.  We  have  found  the 
100-liter  size  to  be  very  serviceable  in  the  clinic.  This  instrument  is 
mounted  on  a  platform  having  rubber  wheels,  and  can-  be  moved  about 
the  wards  with  ease.  The  bell  of  the  spirometer  is  made  of  aluminum 
and  is  suspended  in  a  water-bath  between  the  double  walls  of  a  hollow 
cylinder  made  of  galvanized  iron.  The  height  of  the  bell  is  72  cm. 
and  the  diameter  42  em.  An  opening  at  the  bottom  of  the 
cylinder  connects  through  a  three-way  stopcock  with  the  rubber  tube 
leading   from   the   expiratory   valve   of  the   mouthpiece    (see  Fig.    177). 


MKTIIOD    I'm;     I'l  .TI'.lfMIMMi    RESP1  KATOK  V     EXCHANGE    IX     MAN 


557 


The  bell  is  counterpoised  by  means  of  a  weight.  In  the  original  Tissot 
spirometer  an  automatic  adjustment  permitted  water  in  amounl  equal 
1<>  the  water  displaced  by  the  bell  to  How  from  the  spirometer  cylinder 
into  a   counterpoise   cylinder  as  the   bell   ascended   ou1    of  the   water. 


Fig.    179. — The    Tissot    spirometer.      In    actual    experiment,    subject    is    reclining    or    lying   down    and 
the    valves    and    mouthpiece    are    held    with    a    clamp. 

The  bell,  being  heavier  out  of  water  than  when  it  is  immersed,  is  accord- 
ingly counterpoised  in  any  position,  although  Carpenter  has  shown  that 
this  refinement  is  unnecessary.  An  opening  in  the  top  of  the  spirometer 
permits  the  insertion  of  a  rubber  stopper,  through  which  are  passed  a 
thermometer,  a  water  manometer,  and  a  stopcock  with  tube  for  drawing 


558 


METABOLISM 


the  sample  of  air.    A  scale  on  the  side  of  the  instrument  gives  the  vol- 
ume of  the  air. 

During  an  observation  the  subject  sits  in  a  reclining  position  or  lies 
upon  a  couch.  When  the  hell  of  the  spirometer  is  placed  at  zero,  the 
mouthpiece  adjusted  in  the  mouth,  and  the  nose  clamped,  respiration  is 
started,  the  expirations  being  passed  through  the  stopcock,  which  is 
so  turned  as  to  allow  them  to  pass  to  the  outside  air.  After  a  few- 
minutes  the  stopcock  is  turned  so  that  the  expirations  are  passed  into 


Fig.  180. — The  Douglas  bag  method  for  determining  the  respiratory  exchange.  The  arrange- 
ment of  mouthpiece,  valves,  and  connecting  tubes  shown  here  has  been  found  to  be  more  con 
venient   than   that    recommended   by    Douglas. 

the  spirometer  for  a  definite  length  of  time.  At  the  end  of  the  period 
the  cock  is  again  turned,  and  after  the  barometric  pressure,  temperature, 
and  volume  of  the  air  have  been  noted,  the  composition  of  the  air  is 
determined  in  the  Haldane  gas  analysis  apparatus. 

4.  The  Douglas  Bag. — The  Douglas  bag  is  made  of  rubber-lined  cloth, 
and  is  capable  of  holding  from  50  to  100  liters.  It  is  especially  useful 
for  investigations  during  exercise,  since  it  is  fitted  with  straps  so  that 
the  bag  can  be  fastened  to  the  shoulders  (Fig.  180).  It  is  then  connected 
with  the  valves,  the  mouthpiece   of  which    is   placed   between   the  lips. 


METHOD    FOR    DETERMINING    RESPIRATORY    EXCHANGE   IN    MAN 


559 


Respirations  are  commenced  with  the  three-way  valve  turned  so  as  to 
allow  the  expirations  to  pass  directly  outside.  After  respiratory  equi- 
librium is  established,  the  three-way  valve  is  turned  during  an  inspira- 
tory period  so  that  the  succeeding  expirations  may  pass  into  the  bag. 
The  time  required  to  fill  the  bag  comfortably  is  determined  with  a  stop- 
watch. The  air  which  lias  been  collected  in  the  bag  during  the  period 
is  thoroughly  mixed  and  passed  through  a  meter,  the  temperature  and 
barometric  pressure  are  noted,  and  a  sample  analyzed  in  the  Haldane 


A.  B. 

Fig.    181. — Haldane  gas  apparatus   {A)    and   Pearce   sampling  tube    (B). 

gas-apparatus.     The  bag  should  be  emptied  completely  by  rolling  it  up 
when  nearly  empty. 

5.  The  Haldane  Gas-analysis  Apparatus.  Prixciple. — The  Haldane 
method  of  analysis  of  expired  air  is  simple  and  easily  learned.  The  ap- 
paratus (Fig-.  181)  consists  of  a  gas  burette,  a  control  burette  of  the 
same  size  (both  surrounded  with  a  water  jacket),  and  bulbs  containing 
dilute  caustic  potash  or  soda  solution  for  the  absorption  of  the  carbon  di- 
oxide  and   an  alkaline  pyrogallate  solution  for  the   absorption   of  the 


560  METABOLISM 

oxygen.  The  gas  burette  is  connected  with  the  bulbs  by  a  two-way 
stopcock,  which  allows  a  sample  of  gas  to  pass  into  either  bulb.  A  con- 
trol tube  (10)  is  put  into  connection  with  the  burette  through  a  manometer 
tube,  which  is  connected  with  the  alkali  bulb,  and  can  be  made  to  com- 
pensate for  any  changes  in  temperature  that  may  occur  during  the  course 
of  the  analysis.  For  an  analysis  the  gas  is  transferred  to  the  burette 
from  the  sampling  tube,  saturated  with  Avater  vapor  over  mercury,  and 
then  measured,  after  which  it  is  transferred  into  the  caustic  solution  to 
free  it  from  C02,  and  returned  to  the  burette  to  determine  the  loss  of 
volume  due  to  C02  absorption.  It  is  then  transferred  into  the  alkaline 
pyrogallate  solution,  which  frees  it  from  oxygen,  after  which  it  is  again 
brought  back  to  the  burette  to  determine  the  loss  in  volume  due  to  the 
absorption  of  the  oxygen. 

The  Apparatus. — The  detail  of  the  Haldane  apparatus  is  shown  in 
the  accompanying  cut.  The  measuring  burette  (1)  holds  21  c.c.  The  bulb 
is  of  15  c.c.  capacity,  and  the  graduated  stem,  wrhich  is  about  4  mm.  in 
bore  and  60  cm.  in  length,  is  graduated  to  0.01  c.c.  from  15  c.c.  to  21 
c.c.  The  stopcock  at  the  top  of  the  burette  is  double-bored,  so  that  in 
one  position  air  can  be  drawn  in  from  a  gas  sampler  (2)  and  in  another 
sent  into  the  absorption  bulbs  (3).  The  lower  part  of  the  burette  ex- 
tends through  the  rubber  cork  at  the  bottom  of  the  water  jacket  (4). 
A  piece  of  rubber  tubing  is  attached  to  the  bottom  of  the  burette  and 
is  passed  through  a  metal  tube,  furnished  on  its  inside  with  a  metal  disc 
which  presses  against  the  rubber  tubing,  the  pressure  being  controlled  by 
means  of  a  fine  adjusting  screw  (6).  Below  this  a  glass  stopcock  (7)  con- 
nects with  rubber  tubing  to  the  mercury  leveling  bulb  (5).  The  absorption 
bulb  for  CO,,  containing  20  per  cent  NaOH  or  KOH  (9),  is  put  in  con- 
nection with  the  burette  by  suitably  turning  stopcocks  (3  and  8)*  The 
control  burette  (10)  is  also  in  connection  with  this  bulb  through  the 
manometer  tube  (11). \  Any  variation  in  temperature  which  may  occur 
during  the  analysis  will  cause  the  level  of  the  alkaline  solution  in  the 
manometer  to  change. 

When  final  readings  of  the  shrinkage  of  volume  are  made,  the  level  of 
the  caustic  solution  is  returned  to  the  level  of  that  in  the  manometer. 
By  so  doing  any  error  due  to  temperature  changes  is  avoided,  since 
change  in  temperature  must  be  equal  in  the  two  burettes. 

The  absorption  bulb  for  oxygen  (12)  is  filled  with  a  solution  made  by 
dissolving  10  grams  of  pyogallic  acid  in  100  c.c.  of  a  nearly  saturated 
KOH  solution.  The  specific  gravity  of  the  KOH  should  be  1.55,  which  is 
obtained  approximately  by  dissolving  the  sticks  (pure  by  alcohol)   in  an 


*The  stopcock   (S)   is  double-bored,  so  that  the  tube  leading-  from  the  burette  can  be  brought  into 
connection  with  either  9   or   12. 

fThis  tube  also  has  a  three-way  stopcock  (19),  so  that  it  may  be  opened  to  the  outside. 


METHOD    FOR    DETERMINING    RESPIRATORY    EXCHANGE    IN    MAX  561 

equal  weight  of  water.  The  mark  (13)  on  the  stem  of  llio  bulb  indi- 
cates the  level  a1  which  the  solutions  should  stand.  Enough  pyrogallate 
solution  is  introduced  through  tube  15  to  (ill  bulbs  12  and  14  two-thirds 
full.  Then  pyrogallate  solution  is  poured  into  tube  16  until  Hie  differ- 
ence iu  level  of  the  fluids  is  sufficient  to  produce  enough  pressure  to 
raise  the  level  of  Hie  pyrogallate  solution  in  12  to  the  level  13  on  the 
stem.  Stopcock  8  must  he  open  during  this  procedure.  It  may  be  neces- 
sary to  add  or  take  away  a  little  pyrogallate  solution  through  15  to  at- 
tain the  above  level. 

Care  must  lie  taken  to  allow  for  complete  absorption  of  oxygen  from 
the  air  that  is  entrapped  between  14  and  16  before  an  analysis  is  made; 
otherwise  changes  will  be  produced  in  the  level  of  the  pyrogallate  solu- 
tion. The  aii-  in  the  capillary  tubing  connecting  the  burettes  with  the 
absorption  bulbs  must  also  be  freed  of  C02  and  02.  This  can  be  accom- 
plished by  making  a  dummy  analysis  of  atmospheric  air  before  the  real 
analysis.  Great  care  must  be  taken  to  have  atmospheric  pressure  in  all 
the  tubes  at  the  start  of  the  analysis.  This  is  accomplished  by  opening 
the  stopcock  in  the  burette  first  to  atmospheric  air  and  then  to  the  ab- 
sorption bulbs,  until  no  further  change  in  the  level  of  the  fluids  in  the 
stems,  of  the  absorption  bulbs  occurs.  This  level  is  then  marked  and 
used  as  the  standard.  A  small  amount  of  water  in  the  burette  over  the 
mercury  assures  saturation  of  the  air  with  water  vapor.  Time  for  drain- 
age must  be  allowed  before  making  readings. 

A  very  serviceable  sampling  tube  for  the  transfer  of  air  can  be  made 
from  a  30  c.c.  ground-glass  syringe,  to  which  is  attached  a  two-way 
stopcock.  A  cut  of  this  is  shown  in  Fig.  181.  The  dead  space  in  these 
syringes  is  washed  out  by  working  the  piston  back  and  forth  several 
times.  A  thin  coating  of  vaseline  prevents  leakage  of  the  gas.  We  have 
found  that  these  sampling  tubes  wall  retain  a  sample  of  expired  air  with- 
out change  up  to  eight  hours. 

Manipulation  of  Apparatus. — The  sampling  syringe  (20)  is  attached 
to  opening  2  of  the  burette,  and  its  stopcock  (17)  opened  to  atmospheric  air. 
The  level  of  the  mercury  is  raised  to  the  level  of  the  stopcock  of  the  syringe 
and  is  then  turned  so  that  syringe  and  burette  are  in  communication.  The 
bulb  of  mercury  is  lowered  so  that  the  mercury  falls  in  the  burette.  This 
draws  the  piston  of  the  syringe  with  it,  and  fills  the  burette  with  air 
from  the  syringe.  It  is  advisable  to  put  a  little  positive  pressure  on  the 
piston  of  the  syringe  in  the  maneuver  to  prevent  possible  leakage.  When 
all  of  the  air  is  in  the  burette  a  slight  positive  pressure  is  produced  in 
the  burette  by  gently  pressing  on  the  piston,  and  immediately  there- 
after the  stopcock  on  the  syringe  (17)  is  again  turned  to  the  original 
position.     This  allows  the  pressure  of  air  in  the  burette  to  come  to  that 


562  METABOLISM 

of  the  atmosphere.  The  height  of  the  mercury  is  now  adjusted  to  a  con- 
venient height  in  the  burette  by  closing  cock  7  and  turning  the  milled 
screw  6.  The  cock  18  is  now  made  to  communicate  with  the  absorption 
bulbs.  If  the  air  in  the  burette  is  at  atmospheric  pressure,  no  change 
will  occur  in  the  level  of  the  fluids.  The  reading  is  then  taken  on  the 
burette. 

The  next  step  in  the  analysis  consists  in  turning  stopcock  8  to  com- 
municate with  the  caustic  soda  solution  in  bulb  .9,  and  the  leveling  tube 
(5)  is  raised,  forcing  mercury  into  the  burette  and  the  air  into  bulb  .9. 
The  gas  is  passed  back  and  forth  several  times  until  absorption  is  com- 
plete, as  can  be  determined  by  the  fact  that  the  level  of  the  mercury  in 
the  burette  remains  constant  when  the  fluid  in  the  bulb  is  returned  to 
its  original  level  (1.3)  on  the  stem.  In  this  adjustment  it  is  convenient 
to  make  the  gross  leveling  by  the  mercury  bulb  and  the  fine  leveling  by 
closing  7  and  turning  6  until  the  fluid  in  9  is  at  the  original  height. 
The  reading  on  the  burette  indicates  the  loss  in  volume  due  to  the  C02 
absorbed. 

The  oxygen  is  removed  by  a  similar  procedure,  the  gas  being  passed 
into  the  alkaline  pyrogallate  solution  by  turning  cock  8  to  communicate 
with  bulb  12.  The  absorption  of  oxygen  is  slower  than  for  C02,  and 
more  care  must  be  taken  to  get  complete  absorption.  The  air  in  the 
tubing  between  the  fluid  in  9  and  stopcock  8  must  be  washed  out  sev- 
eral times  in  order  to  get  the  oxygen  which  is  left  in  it  after  the  absorp- 
tion of  the  C02.  When  this  is  complete,  the  final  reading  on  the  burette 
is  made  and  the  loss  in  volume  from  the  second  reading  represents  the 
oxygen. 

THE  CALCULATIONS 

The  calculation  of  the  percentile  composition  of  the  air  and  of  the  re- 
spiratory quotient  is  represented  in  the  following  example  of  an  actual 
analysis : 

(The  temperature  and  barometric  pressure  as  taken  at  the  time  of  the 
experiment  were  20°  C.  and  747  mm.  Hg.) 

CO..  analysis — 

1st  reading  of  burette    20.00 

2nd  reading  of  burette  after  absorption  of  CO. 19.20 

C02    absorbed    0.80 

0.80-^20  =  4.0  per  cent  CO,  in  expired  air. 

02  analysis — ■ 

2nd  reading   of   burette 19.20 

3rd  reading  of  burette  after  absorption  of  O, 15.90 

O,  absorbed    3.30 

3.30  -f-  20  =  16.50  per  cent  of  02  in  expired  air. 


METHOD    FOR    DETERMINING    RESPIRATORY    EXCHANGE    l\    MAN  fill:'. 

I>,h  iiniimlimt   Of   i:.Q. — 

(\  in   atmospheric  air  =  20.94% 

o"     CO,  in  expired  air  (16.50  l  4)  =20.50% 

KHi- 20.04  =  79.0(1',;,    X   in  atmospheric  air. 
100-20.50  =  79.50%,    N  in  expired   air. 

Since  the  nitrogen  is  nol  changed  in  volume,  the  last  figure  shows  thai 

more  oxygen  must  have  been  taken  in  during  inspiration  than  ()..  hCO 
has  been  given  hack  in  expiration.     This  obviously  must  be  taken  into 
account  in  the  calculations.     The  amount  of  02  actually  inspired   for  each 
100  c.c.  of  air  expired  is  found  as  follows: 

20.94   (%  0,  in  atmospheric  air) 

„n  Ag   /rrl    „*    . 7 \ — = — *     X  79.50   (%    N .  in   expired   air);   or  0.2G5    (con 

79.06  (%  N2  in  atmospheric  air)     /x  v  /a      -  ' 

stant  factor  X  79.5  i  ' ',   N  found  for  tliis  observation)  =21.07,  the  volume  of  (X  which 

would  have  been  present  in  expired  air  to  account  for  N  present. t 

21.07-16.50  =  4.57%  O,  actually  absorbed. 

t.00     0.03   (CO,  in  inspired  air)  z=  3.97$   CO,  excreted. 

3.97 

=  0.87,  the  respiratory  quotient,  or  ratio  of  C02  excreted  to  02  absorbed. 


4.57 


Total  Gas  Exchange. — The  volume  of  air  expired  in  15  minutes  into 
the  Tissot  spirometer  was  found  to  be  100  liters  measured  at  20°  C.  and 
747  mm.  Hg  (brass-scale  barometer).  This  volume  of  gas  must  be  cor- 
rected so  as  to  give  the  volume  of  dry  air  at  0°  and  760  mm.  Tig.  To  do 
this  two  things  must  be  taken  into  account.  (1)  Since  the  expired  air  is 
saturated  with  water,  the  pressure  due  to  water  vapor  must  be  subtracted 
from  the  observed  barometric  pressure  to  obtain  the  true  pressure.  The 
vapor  tension  of  water  for  various  temperatures  is  given  in  Table  II 
on  page  564..  (2)  The  barometer  tube  lengthens,  or  contracts  with  heat 
or  cold,  and  therefore  the  barometric  readings  must  be  corrected. 
The  corrections  for  ordinary  barometric  readings  are  found  in  Table  III, 
page  565.  The  figure  corresponding  to  the  temperatures  is  subtracted 
from  the  barometric  reading  in  order  to  obtain  correct  barometric  pres- 
sure. 

In  the  above  experiment,  the  correction  for  the  barometer  is  2.41  mm. 
i  see  Table  III,  page  565),  and  that  for  vapor  tension  at  20°  C.  is  17.4 
(see  Table  II,  page  564^. 

Actual  Barometric  Pressure.— 747-  (17.5  4-2.39)  =727.21  mm.  The 
coefficient  of  expansion  of  gases  is  taken  as  0.003665)  or  1/273;  therefore 
the  volume  of  0°  equals  the  volume  at  1°  divided  by  1-0.003665  t;  and 
hence 


*'fhis  is  the  constant   O  percentage  in  air. 

t'fhis  calculation  can  be  simplified  by  using  an  abbreviated  table   (page  564)  giving  the  02  figure 
corresponding  to  the  various  percentages  of  N  in  the  expired  air. 


564  METABOLISM 

V  X  273  V 

Vo  =  -— = n  n^^  ,„„ —   ,  when  Vo  =  Volume  at  0°  and  V  =  Volume  at  t°. 

273  + 1       1  +  0.0036G5  t 

VP 

The  volume  of  gas  being  inversely  as  the  pressure,  Vo  = where  V  =  volume  at 

760 
P  pressure ;  or  working  both  corrections  together, 

VPx273  VP 


Vo  = 


760  x  (273  +  t)  —  760  (1  +  0.003665  t) 


This  formula  applied  to  the  present  problem  reads: 


v  100x727.2  on  or* 

Vo  =  , =  89.2  liters. 

760  (1  +  0.003665x20) 

The  latter  calculation  can  be  considerably  simplified  by  using  standard 
tables  which  give  constants  for  corrections  of  gas  volumes.  These  are 
easily  obtainable  and  are  given  in  part  in  Table  IV. 

According  to  these  tables  for  20°  C.  and  727.21  mm.  Hg  B.P.,  the 
factor  is  0.89124;  therefore: 

0.89124  x  100  =  89.124  liters,  0°C.  and  760  mm.  Hg. 
0.89124x4.57  =  40.7  liters  of  0„  in  15  min.,  or  16.28  L.  per  hour. 

The  Caloric  Value  Calculated  from  the  Gas  Exchange. — By  reference 
to  Table  V  giving  the  heat  value  of  1  liter  of  02  at  various  respiratory 
quotients,  it  is  found  that  at  a  R.Q.  of  0.87,  4.888  calories  are  expended ; 
16.28  liters  of  02  is  therefore  equivalent  to  18.4  x  4.888  =  79  calories. 

The  results  must  be  calculated  for  surface  area  as  well  as  body  weight. 
Suppose  the  subject  weighed  85  kg.  and  was  170  cm.  in  height;  by  refer- 
ence to  the  chart  for  determining  the  surface  area  of  man  (page  540), 
this  would  be  found  to  be  1.96  square  meters.     The  caloric  expenditure 

79 
per  square  meter  in  the  above  case  is  therefore    .,  .  .    =  40.3  calories. 

1.9b 

Table  I 

The  Percentage  of  Oxygen  which  is  Equivalent  to  the  Nitrogen  Found  in  the 

Expired  Air 

To  obtain  the  nitrogen  in  the  expired  air,  add  the  percentage  of  C02  and  02  found 
and  subtract  the  sum  from  100.  The  table  gives  the  percentage  for  02  corresponding  to 
this  figure: 


%N, 

7S.7 

78.8 

78.9 

79.0 

79.1 

79.2 

79.3 

79.4       79.5 

79.6 

79.7 

79.8 

%o. 

20.86 

20.88 

20.90 

20.93 

20.96 

20.98 

21.01 

21.04    21.07 

21.10 

21.12 

21.14 

79.9 

80.0 

80.1 

80.2 

S0.3 

S0.4 

80.5 

80.6 

21.16 

21.19 

21.22 

21.25 

21.28 

21.31 

21.35 

21.38 

Table  II 
Tension  of  Aqueous  Vapor  in  Millimeters  of  Mercury 
To  obtain  the  dry  barometer  pressure,  subtract  the  mm.  Hg.  corresponding  to  the 
temperature  of  the  air  from  the  barometer  pressure  at  the  time  of  the  experiment: 

Temp.       15°         16°         17°         18°         19°         20°         21°         22°         23°         24°         25° 
Mm.  12.7       13.5       14.4       15.4        16.3       17.4        18.5       19.7       20.9        22.2       23.5 


METHOD  FOR   DETERMINING    RESPIRATORY    EXCHANGE    l.\    MAN  5G5 

Table  HI 
Temperature  Corrections  to  Reduce  Readings  ok  a  Mercurial  Barometer  with  a 

I'.i;  \ss  Scale  to  0°C. 
Subtract  the  appropriate  quantity  BS  found  in  table  from  the  beighi  of  the  barometer. 
Tlie  table  is  for  a  barometer  with  a  brass  scale,  and  the  values  arc  a  little  lower  (about 
.'2  mm.)  than   for  the  glass  scale.     The  corrections  for  intermediate  temperatures  can  be* 
approximated. 


Temp. 

700 
mm. 

710 
mm. 

720 
mm. 

730 
mm. 

740 
mm. 

750 
mm. 

760 
mm. 

770 
mm. 

15° 
20° 
25° 

1.69 
2.26 
2.83 

1.72 
2.22 
2.87 

1.74 
2.32 
2.91 

1.77 

2.36 
2.05 

1.79 
2.39 
2.99 

1.81 

2.42 

'  3.03 

1.84 
2.45 

3.07 

1.86 
2.48 
3.11 

Table  IV 
Table  for  Reducing  Gaseous  Volumes  to  Normal  Temperature  and  Pressure 
The  observed  volume,  when  multiplied  by  the  factor  corresponding  to  the  temperature 
and  pressure,  will  give  the  volume  of  the  expired  air  reduced  to  0°  and  700  mm. 

MmT       15°  16°         17°  18"  1~9°         20°         21°         22°         23°         24°         25°" 


720 

.898 

.894 

.891 

.888 

.885 

.882 

.ssi) 

.877 

.873 

.870 

.867 

730 

.910 

.907 

.904 

.901 

.897 

.894 

.891 

.888 

.885 

.882 

.879 

740 

.922 

.919 

.916 

.913 

.910 

.907 

.904 

.901 

.897 

.894 

.891 

750 

.935 

.932 

.928 

.925 

.922 

.919 

.916 

.913 

.910 

.907 

.904 

760 

.947 

.944 

.941 

.938 

.934 

.931 

.928 

.925 

.922 

.919 

.916 

770       .960        .957        .953        .950        .948        .945        .940        .936        .933        .930        .927 

Table  V 

R.  Q.  CALORIES  FOR  1  LITER  02  RELATIVE  CALORIES  CONSUMED  AS 

Number                   Carbohydrate  Fat 

per  cent  per  cent 

~0~  "loo"- 

1.4  98.6 

4.8  95.2 

8.2  91.8 

11.6  8S.4 

15.0  85.0 

18.4  81.6 

21.8  78.2 

25.2  74.8 

28.6  71.4 

32.0  68.0 

35.4  64.6 

38.8  61.2 

42.2  57.8 

45.6  54.4 

49.0  51.0 

52.4  47.6 

55.8  44.2 

59.2  40.8 

62.6  37.4 

66.0  34.0 

69.4  30.6 

72.8  27.2 

76.2  23.8 

79.6  20.4 

83.0  17.0 

86.4  13.6 

89.8  10.2 

93.2  6.8 

M.(\  3.4 

100.0  0.0        

(From  Lusk.) 


0.707 

4.686 

0.71 

4.690 

0.72 

4.702 

0.73 

4.714 

0.74 

4.727 

0.75 

4.739 

0.76 

4.752 

0.77 

4.764 

0.78 

4.776 

0.79 

4.789 

0.80 

4.801 

0.81 

4.813 

0.S2 

4.825 

0.83 

4.838 

0.84 

4.850 

0.85 

4.863 

0.86 

4.875 

0.87 

4.S87 

0.88 

4.900 

0.89 

4.912 

0.90 

4.924 

0.91 

4.936 

0.92 

4.948 

0.93 

4.9(50 

0.94 

4.973 

0.95 

4.985 

0.96 

4.997 

0.97 

5.010 

0.98 

5.022 

0.99 

5.034 

1.00 

5.047 

CHAPTER  LXIII 
STARVATION 

In  order  to  furnish,  us  with  a  standard  with  which  Ave  may  compare 
other  conditions,  Ave  shall  first  of  all  study  the  metabolism  during  starva- 
tion. A  valuable  chart  compiled  from  observations  made  in  the  Carne- 
gie Institution  of  Washington  on  a  man  Avho  fasted  for  thirty-one  days 
is  reproduced  in  Fig.  182. 

The  Excretion  of  Nitrogen. — When  an  animal  is  starved,  it  has  to 
live  on  its  own  tissues,  but  in  doing  so  it  saves  its  protein,  so  that  the 
excretion  of  nitrogen  falls  after  a  feAv  days  to  a  Ioav  level,  the  energy 
requirements  being  meaiiAvhile  supplied,  so  far  as  possible,  from  stored 
carbohydrate  and  fat.  Although  always  small  in  comparison  Avith  fat, 
the  stores  of  carbohydrate  vary  considerably  in  different  animals.  Tliey 
are  much  larger  in  man  and  the  herbivora  than  in  the  carnivora.  Dur- 
ing the  first  few  days  of  starvation  it  is  common,  in  the  herbivora,  to  find 
that  the  excretion  of  nitrogen  is  actually  greater  than  it  Avas  before 
starvation,  because  the  custom  has  become  established  in  the  metabolism 
of  these  animals  of  using  carbohydrates  as  the  main  fuel  material,  so 
that  when  carbohydrates  are  withheld,  as  in  starvation,  proteins  are 
used  more  than  before  and  the  nitrogen  excretion  becomes  greater.  We 
may  say  that  the  herbivorous  animal  has  become  carnivorous.  The  same 
thing  may  occur  in  man  when  the  previous  diet  Avas  largely  carbohy- 
drate; thus,  almost  invariably  in  man  the  nitrogen  output  is  larger  on 
the  third  and  fourth  days  of  starvation  than  on  the  first  and  second. 

Another  factor  influencing  the  nitrogen  excretion  during  the  early 
days  of  the  fast  is  the  amount  of  previous  intake  of  nitrogen;  the  greater 
this  has  been,  the  greater  the  excretion.  By  the  seventh  day,  liOAvever,  a 
uniform  output  of  nitrogen  will  usually  be  reached  irrespective  of  the 
individual's  protein  intake.  During  the  greater  part  of  starvation,  most 
of  the  energy  required  to  maintain  life  is  derived  from  fat,  as  little  as 
possible  being  derived  from  protein.  This  type  of  metabolism  lasts  until 
all  the  available  resources  of  fat  have  become  exhausted,  when  a  more 
extensive  metabolism  of  protein  sets  in,  Avith  the  consequence  that  the 
nitrogen  excretion  rises.  This  is  really  the  harbinger  of  death — it  is  often 
called  the  premortal  rise  in  nitrogen  excretion.  It  indicates  that  all  the 
ordinary  fuel  of  the  animal  economy  has  been  used  up,  and  that  it  has 

566 


STARVATION 


567 


[NUTRITION  LABORATORY  OF  THE  CARNEGIE  INSTITUTION  OF  WASHINGTON.  BOSTON.  MASSACHUSETTS] 

METABOLISM  CHART  OF  A  MAN  FASTING  31  DAYS 

APRIL  14 -MAY  15.  1912 


3   4    5    6    7   8    9   10  II  12  13  14  15  16  17  18  192021  22  232;*  25  36  27  28  29  30  31 


OXYGEN  AND  CARBON 
DIOXIDE,  c.c 


ALVEOLAR  CO,  TENSION. 


81000  PRESSURE. m«. 


HEAT  PER  24  HRS.CALS. 


BODY  TEMPERATURE.  "C 


WAT  PERNIO. PER  HR.CALJ. 


RESPIRATORY  QUOTIENT 


RESPIRATION  RATE 
PULSE  RATE 


CHLORINE  (CI).  GMS. 


TOTAL  NITROGEN.  GMS. 


PHOSPHORUS  (P,Os).  GMS, 

CARBON  IN  URINE.  GMS.  1 
B-OXYBUTYRIC  ACID.  CMS.) 


URICACIO-N.GM. 
TOTAL  SULPHUR  (S).  CM 

AMMONIA-N.  GMS. 


7  8  9  10  II  12  13  14  15  16  17  18  19  20  21  22  23  2*25  26  27  28  29  30  3> 


Fig  182. — Curve  constructed  from  data  obtained  from  a  man  who  fasted  for  thirty-one  days. 
The  days  of  the  fast  are  given  along  the  abscissae,  and  the  various  measurements  along  the  or- 
dinates.     (From   F.  G.   Benedict.) 


568  METABOLISM 

become  necessary  to  burn  the  very  tissues  themselves  in  order  to  obtain 
sufficient  energy  to  maintain  life.  Working  capital  being  all  exhausted, 
an  attempt  is  made  to  keep  things  going  for  a  little  longer  time  by  liq- 
uidation of  permanent  assets.  But  these  assets,  as  represented  by  pro- 
tein, are  of  little  real  value  in  yielding  the  desired  energy  because,  as 
vre  have  seen,  only  4.1  calories  are  available  against  9.3,  obtainable 
from  fats. 

These  facts  explain  why  during  starvation  a  fat  man  excretes  daily 
less  nitrogen  than  a  lean  man,  and  why  the  fat  man  can  stand  the  starva- 
tion for  a  longer  time.  The  premortal  rise  is,  however,  not  prevented  by 
feeding  oil,  which  would  seem  to  indicate  that  death  may  be  due  not  so 
much  to  the  absence  of  fuel  as  to  serious  nutritional  disturbance  of  es- 
sential organs;  e.  g.,  there  may  be  no  available  material  to  supply  the 
glands  of  internal  secretion  with  the  building  stones  they  must  have 
(see  page  580). 

Not  only  is  there  this  general  saving  of  protein  during  starvation, 
but  there  is  also  a  discriminate  utilization  of  what  has  to  be  used  by  the 
different  organs,  according  to  their  relative  activities.  This  is  very 
clearly  shown  by  comparison  of  the  loss  of  weight  which  each  organ  un- 
dergoes during  starvation.  The  heart  and  brain,  which  must  be  active  if 
life  is  to  be  maintained,  lose  only  about  3  per  cent  of  their  original 
weight,  whereas  the  voluntary  muscles,  the  liver  and  the  spleen  lose 
31,  54  and  67  per  cent,  respectively.  No  doubt  some  of  this  loss  is  to 
be  accounted  for  as  due  to  the  disappearance  of  fat,  but  a  sufficient 
remainder  represents  protein  to  make  it  plain  that  there  must  have  been 
a  mobilization  of  this  substance  from  tissues  where  it  Avas  not  absolutely 
necessary,  such  as  the  liver  and  voluntary  muscles,  to  organs,  such  as  the 
heart,  in  which  energy  transformation  is  sine  qua  non  of  life.  The  vital 
organs  live  at  the  expense  of  those  whose  functions  are  accessory. 

The  energy  output  per  square  meter  of  body  surface  steadily  declines. 
In  the  man  examined  by  Benedict,  it  was  958  C.  per  square  meter  of 
surface  at  the  end  of  the  first  twenty-four  hours,  but  only  737  on  the 
thirty-first  day  of  the  starvation  period.  The  oxygen  intake  and  carbon- 
dioxide  output  correspondingly  diminish. 

The  behavior  of  the  nitrogenous  metabolites  in  the  urine  is  of  par- 
ticular interest,  the  following  facts  being  of  significance:  Urea  nitrogen 
relatively  falls  and  NH3  -  N  rises.  For  example,  on  the  last  day  of  feeding 
the  percentage  output  of  NH3  -  N  in  relation  to  total  nitrogen  was  3.16; 
on  the  eighth  day  of  the  fast  it  was  14.88  (Cathcart).2  Acidosis  is  the 
cause.  The  total  amount  of  creatinine  and  creatine  shows  only  a  slight 
fall,  but  creatinine  relatively  decreases  and  creatine  increases  (Cathcart). 
Since  creatine  is  a  substance  peculiar  to  muscle  tissue,  it  is  possible  by 


STARVATION  569 

comparing  the  creatine  and  creatinine  outpul  with  that  of  nitrogen  to 
determine  -whether  all  of  the  nitrogen  Liberated  by  the  breakdown  of 
muscle  has  been  excreted,  or  whether  some  has  been  retained  either  for 
resynthesis  in  the  muscle  itself  or  for  use  elsewhere.  If  the  muscle 
breakdown  as  calculated  from  the  creatine-creatinine  output  is  greater 
than  that  calculated  from  the  nitrogen,  synthesis  of  the  noncreatine 
remainder  must  be  occurring;  whereas  if  the  breakdown  calculated  from 
nitrogen  is  greater  than  that  calculated  from  creatine,  etc.,  other  tis- 
sues than  muscle  must  be  contributory.  Stored  nitrogen  or  free  nitro- 
gen in  transit  from  tissue  to  tissue  for  utilization  is  the  most  likely 
source  of  such  excess  nitrogen. 

That  transference  of  nitrogenous  substances  from  place  to  place  in  the 
body  in  starvation  is  proved  (1)  by  the  constant  presence  of  amino  ni- 
trogen in  the  blood  and  tissues  (Van  Slyke)  ;  and  (2)  by  the  effect  of 
copious  water  drinking.  The  latter  causes  a  decided  increase  in  the  out- 
put of  nitrogen,  but  it  does  not  appear  that  the  extra  nitrogen  is  due  to 
increased  protein  breakdown.  It  is  probable,  however,  that  in  such  cases 
there  would  also  be  an  increase  in  endogenous  protein  metabolism,  since 
the  washed-out  free  nitrogen  would  have  to  be  replaced. 

Excretion  of  Purines. — Although  at  first  they  fall  somewhat,  the  total 
amount  increases  as  the  fast  progresses.  Perhaps  the  first  decline  is 
due  to  general  using  up  of  hypoxanthine  of  muscle  and  the  later  rise 
to  the  breakdown  of  nuclei  (page  638). 

Excretion  of  Sulphur. — It  is  important  to  compare  the  excretion  of 
sulphur  and  nitrogen.  In  the  early  days  of  starvation  a  ratio  of  17  N :  1  S 
has  been  found,  but  later  one  of  14.5:  1,  which  is  practically  the  same 
as  that  in  muscle  (i.e.,  14;  1),  indicating  that  late  in  fasting  the  main 
source  of  protein  supply  is  muscle. 

Several  of  the  changes  observed  during  starvation  can  be  attributed 
to  the  condition  of  acidosis  which  supervenes.  The  acids  are  derived 
from  incomplete  combustion  of  fat  (see  page  683),  and  are  represented 
by  0-oxybutyric,  the  amount  being  sometimes  considerable  (10-15  grams 
a  day),  especially  in  obese  individuals.  The  large  ammonia  excretion 
(sometimes  2  grams  a  day)  is  evidently  for  the  purpose  of  neutralizing 
the  excess  of  acid.  Another  consequence  of  the  acidosis  is  the  decline 
in  the  alveolar  tension  of  C02  (page  354),  and  it  is  possible  that  some  of 
the  circulatory  changes  shown  in  the  chart  may  also  be  dependent  on 
it.  The  method  of  repeated  fasting  used  for  reducing  obesity  is  quite 
safe  if  the  acidosis  is  carefully  watched. 

Many  secondary  changes  also  occur  in  the  starving  organism.  Thus, 
the  mobilization  of  fat  is  often  responsible  for  a  pronounced  increase  in 
the  fat  content  of  the  blood  (see  page  698),  and  that  of  protein  explains 


570  METABOLISM 

the  presence  of  an  amount  of  amino  nitrogen  no1  much  below  that  of 
normal  animals  (viz.,  4  mg.  per  100  c.c.  of  blood).  Similarly  with 
carbohydrates,  early  in  the  condition  the  blood  sugar  becomes  much 
lower  than  normal,  but  then  remains  steady.  This  is  significant  Avhen 
we  remember  that  after  two  or  three  days  of  starvation  all  of  the  avail- 
able glycogen  has  been  used  up.  It  indicates  that  carbohydrate  must 
be  essential  for  life,  and  that  it  is  produced  in  starvation  from  proteins 
(see  page  667). 

Starvation  ends  in  death  in  an  adult  man  in  somewhat  over  four 
weeks  but  much  sooner  in  children,  because  of  their  more  active  metab- 
olism. At  the  time  of  death  the  body  weight  may  be  reduced  by  50  per 
cent.  The  body  temperature  doe's  not  change  until  Avithin  a  few  days 
of  death,  when  it  begins  to  fall,  and  it  is  undoubtedly  true  that  if  means 
are  taken  to  prevent  cooling  of  the  animal  at  this  stage,  life  will  be 
prolonged. 

Death  from  starvation  must  be  due  either  to  a  general  failure  of  all 
the  cells  or  to  injury  of  certain  organs  that  are  essential  for  life.  Since 
the  loss  of  protein  from  the  body  as  a  whole  may  vary  between  20  and 
50  per  cent  at  the  time  of  death  by  starvation,  it  is  unlikely  that  general 
failure  can  be  its  cause.  If  it  were  so,  death  would  always  occur  when 
some  fixed  loss  of  protein  had  occurred.  Certain  organs  evidently  cease 
to  perform  their  function,  either  because  they  are  deprived  of  raw  mate- 
rial for  the  elaboration  of  some  substance  (hormone)  necessary  for  life, 
or  because  the  organs  themselves  wear  out  from  want  of  nourishment. 

NORMAL  METABOLISM 

Apart  from  the  practical  importance  of  knowing  something  about  the 
behavior  of  an  animal  during  starvation,  such  knowledge  is  of  great 
value  in  furnishing  a  standard  with  which  to  compare  the  metabolism 
of  animals  under  normal  conditions.  Taking  again  the  nitrogen  balance 
as  indicating  the  extent  of  protein  wear  and  tear  in  the  body,  let  us 
consider  first  of  all  the  conditions  under  which  equilibrium  may  be  re- 
gained. It  would  be  quite  natural  to  suppose  that,  if  an  amount  of  pro- 
tein containing  the  same  amount  of  nitrogen  as  is  excreted  during 
starvation  were  given  to  a  starving  animal,  the  intake  and  output  of 
nitrogen  would  balance.  We  are  led  to  make  this  assumption  because  we 
know  that  any  business  balance  sheet  showing  an  excess  of  expenditure 
over  income  could  be  met  by  such  an  adjustment.  But  it  is  a  very  differ- 
ent matter  with  the  nitrogen  balance  sheet  of  the  body;  for,  if  we  give 
the  starving  animal  just  enough  protein  to  cover  the  nitrogen  loss,  we 
shall  cause  the  excretion  to  rise  to  a  total  which  is  practically  equal  to 


STARVATION  571 

the  starvation  amounl  plus  all  that  we  have  given  as  food;  and  although 
by  daily  giving  this  amounl  of  protein  there  may  be  a  slight  decline  in 
the  excretion,  it  will  never  come  near  to  being  the  same  as  that  of  the 
intake.  The  only  effect  of  such  feeding  will  he  to  prolong  life  for  a 
few  days. 

Nitrogenous  Equilibrium. — To  attain  equilibrium  we  must  give  an 
amount  of  protein  whose  nitrogen  content  is  at  least  two  and  one-half 
times  that  of  the  starvation  level.  For  a  few  days  following  the  estab- 
lishment of  this  pure  protein  did.  the  nitrogen  excretion  will  be  far  in 
excess  of  the  intake,  but  it  will  gradually  decline  until  the  two  practically 
correspond.  Having  once  gained  an  equilibrium,  we  may  raise  its 
level  by  gradually  increasing  Hie  protein  intake.  During  this  progres- 
sive raising  of  the  ingested  protein,  it  will  be  found,  at  least  in  the  car- 
nivora  (cat  and  dog),  that  a  certain  amount  of  nitrogen  is  retained  by 
the  body  for  a  day  or  so  immediately  following  each  increase  in  pro- 
tein intake.  The  excretion  of  nitrogen,  in  other  words,  does  not  immedi- 
ately follow  the  dietetic  increase.  The  amount  of  nitrogen  thus  retained  is 
too  great  to  be  accounted  as  a  retention  of  disintegration  products  of 
protein ;  it  must  therefore  be  due  to  an  actual  building  up  of  new  pro- 
tein tissue — that  is,  growth  of  muscles. 

Nitrogenous  equilibrium  on  a  protein  diet  alone  is  readily  attainable 
in  the  cat,  and  less  readily  in  the  dog.  But  in  man  and  the  herbivorous 
animals,  it  is  impossible  to  give  a  sufficiency  of  protein  alone  to  maintain 
equilibrium;  there  will  always  be  an  excess  of  excretion  over  intake. 
Indeed  it  scarcely  requires  any  experiment  to  prove  this,  for  it  is  self- 
evident  when  we  consider  that  there  are  less  than  1000  C  in  a  pound  of 
uncooked  lean  meat,  and  that  there  are  few  who  could  eat  over  three 
pounds  a  day,  an  amount,  hoAvever,  which  Avould  scarcely  furnish  all  of 
the  required  calories.  A  person  fed  exclusively  on  flesh  is  therefore 
being  partly  starved,  even  although  he  may  think  that  he  is  eating 
abundantly  and  be  quite  comfortable  and  active.  This  fact  has  a  prac- 
tical application  in  the  so-called  Banting  care  for  obesity. 

Protein  Sparers. — Very  different  results  are  obtained  when  carbohy- 
drates or  fats  are  freely  given  with  the  protein  to  the  starving  animal. 
Nitrogen  equilibrium  can  then  be  regained  on  very  much  less  protein, 
so  that  we  speak  of  fats  and  carbohydrates  as  being  "protein  sparers." 
Carbohydrates  are  much  better  protein  sparers  than  fats;  indeed  they 
are  so  efficient  in  this  regard  that  it  is  now  commonly  believed  that  car- 
bohydrates are  essential  for  life,  and  that  when  the  food  contains  no 
trace  of  carbohydrates,  a  part  of  the  carbon  of  protein  has.  to  be  con- 
verted into  carbohydrate.  This  important  truth  is  supported  by  evi- 
dence derived  from  other  fields  of  investigation  (e.  g.,  the  behavior  of 


572  METABOLISM 

diabetic  patients,  in  -whom  the  power  to  use  carbohydrates  is  greatly 
depressed).  The  marked  protein-sparing  action  of  carbohydrates  is  il- 
lustrated in  another  way — namely,  by  the  fact  that  we  can  greatly 
diminish  the  protein  breakdown  during  starvation  by  giving  carbo- 
hydrates. In  this  way  we  can  indeed  reduce  the  daily  nitrogen  excre- 
tion to  about  one-third  its  amount  in  complete  starvation.  Carbohy- 
drate starvation  is  said  to  entail  a  failure  of  the  muscles  to  use  again  in 
their  metabolism  certain  of  the  products  (e.  g.,  creatine)  which  result 
from  their  disintegration.  At  any  rate  it  has  been  found  that  creatine 
is  excreted  in  the  urine  when  no  carbohydrates  are  available. 

In  the  case  of  man  living  on  an  average  diet,  although  the  daily  nitro- 
gen excretion  is  about  15  grams,  it  can  be  lowered  to  about  6  grams 
provided  that  in  place  of  the  protein  that  has  been  removed  from  the 
diet  enough  carbohydrate  is  given  to  bring  the  total  calories  up  to  the 
normal  daily  requirement.  If  an  excess  of  carbohydrate  over  the  energy 
requirements  is  given,  the  protein  may  be  still  further  reduced  with- 
out disturbing  the  equilibrium.  It  has  been  found  that  it  is  not  the 
amount  of  carbohydrate  alone  that  determines  the  ease  with  which  the 
irreducible  protein  minimum  can  be  reached;  the  kind  of  protein  itself 
makes  a  very  great  difference.  This  has  been  very  clearly  shown  by 
one  investigator,  who  first  of  all  determined  his  nitrogen  excretion  while 
living  exclusively  on  starch  and  sugar,  and  who  then  proceeded  to  see  how 
little  of  different  kinds  of  protein  he  had  to  take  in  order  to  bring  him- 
self into  nitrogenous  equilibrium.  He  found  that  he  had  to  take  the 
following  amounts:  30  gm.  meat  protein,  31  gm.  milk  protein,  34  gm. 
rice  protein,  38  gm.  potato  protein,  54  gm.  bean  protein,  76  gm.  bread 
protein,  and  102  gm.  Indian-corn  protein.  The  organism  is  evidently 
able  to  satisfy  its  protein  demands  much  more  readily  with  meat  than 
with  vegetable  proteins. 

This  variability  in  the  food  value  of  different  proteins  depends  on  their 
ultimate  structure — that  is,  on  the  proportion  and  manner  of  linkage 
of  the  various  amino  acids  that  go  to  build  up  the  molecule.  In  no  two 
proteins  are  these  building  stones,  as  they  are  called,  present  in  exactly 
the  same  proportions,  some  proteins  having  a  preponderance  of  one  or 
more  and  an  absence  of  others,  just  as  in  a  row  of  houses  there  may  be 
no  two  that  are  exactly  alike,  although  for  all  of  them  the  same  build- 
ing materials  were  available.  Albumin  and  globulin  are  the  most  im- 
portant proteins  of  blood  and  tissues,  so  that  the  food  must  contain  the 
necessary  units  for  their  construction.  If  it  fails  in  this  regard,  even  to 
the  extent  of  lacking  only  one  of  the  units,  the  organism  will  either  be 
unable  to  construct  that  protein,  and  will  therefore  suffer  from  partial 
starvation,  or  it  will  have  to  construct  for  itself  this  missing  unit.     It 


STARVATION  573 

is  therefore  apparenl  thai  the  mosl  valuable  proteins  will  be  those  that 
contain  ;ni  array  of  units  thai  can  be  reunited  to  form  all  the  varieties 
of  protein  entering  into  the  structure  of  the  body  proteins.  Naturally, 
the  protein  which  most  nearly  meets  the  requirements  is  meat  protein, 

so  that    we  are  not   surprised  to  find  that    less  of  this  than   of  any  other 

protein  lias  to  be  taken  to  gain  nitrogen  equilibrium. 

The  most  exact  information  regarding  the  "food  value"  of  different 
proteins  has  been  secured  by  observations  on  the  rate  of  growth  of  young 
animals.  This  method  yields  more  reliable  information  than  ean  be 
secured  by  studies  on  the  nitrogenous  balance,  because  it  is  not  usually 
possible  to  keep  up  the  latter  observations  for  a  sufficient  period  of 
time,  or  to  secure  an  adequate  number  of  data.  During  growth  the 
building-up  processes  are  in  excess  of  the  breaking-down,  so  that  the 
effect  is  an  increase  in  bulk  of  the  tissues,  thus  permitting  us,  by  the  sim- 
ple expedient  of  observing  the  body  weight,  to  draw  conclusions  as  to 
the  influence  of  various  foodstuffs  on  tissue  construction. 


CHAPTER  LXIV 

NUTRITION  AND  GROWTH 

In  the  grow tli  of  animal  tissues  two  factors  are  concerned,  one  being 
the  property  of  the  cell  to  grow,  the  growth  factor;  and  the  other,  the 
availability  of  suitable  material  to  grow  upon,  the  food  factor.  Concern- 
ing the  growth  factor  little  is  known ;  its  variability  in  different  species 
of  animal,  its  irregularity  despite  proper  adjustment  of  the  food  factors, 
its  abnormality  leading  to  tumor  formation,  etc.,  are  all  well-known  bu1 
apparently  inexplicable  facts  (Mendel8). 

THE  FOOD  FACTOR  OF  GROWTH 

Our  knoAvledge  is  constantly  increasing  concerning  the  food  factor  of 
growth,  and  many  facts  of  extreme  practical  importance  have  been  ac- 
cumulated in  recent  years.  In  seeking  for  the  relationship  of  food  to 
growth,  we  must  first  of  all  consider  whether  this  process  entails  a 
greater  expenditure  of  energy  than  is  necessary  for  mere  maintenance 
in  adult  life.  Important  results  bearing  on  this  question  have  been  se- 
cured by  observations  on  the  basal  metabolism  of  young  children.  In 
computing  the  energy  supply  of  fasting  adult  animals  of  different  sizes, 
it  will  be  remembered  that  the  smaller  the  animal,  the  greater  is  the 
energy  exchange  in  relationship  to  the  body  weight,  although  when 
computed  in  relationship  to  body  surface  tolerably  constant  values  are 
obtained.  When  the  calorie  output  per  square  meter  is  determined  in 
growing  children,  there  is,  as  we  have  already  seen,  clear  evidence  of 
greater  energy  expenditure  (see  page  541),  particularly  marked  in  boys 
just  before  puberty.  An  increased  energy  metabolism  has  also  been  de- 
scribed in  the  case  of  infants,  but  the  uncontrollable  muscular  activity, 
the  psychic  disturbances,  etc.,  may  explain  the  result.  Even  after  dis- 
counting these  factors,  however,  it  is  possible  that  there  may  be  a  cer- 
tain influence,  depending  probably  on  the  active  mass  of  growing  proto- 
plasmic tissue,  which  stimulates  the  energy  expenditure.  The  question 
is  not  yet  finally  settled. 

The  Relationship  of  Proteins  to  Growth  and  Maintenance  of  Life. — 
Since  protein  constitutes  the  fundamental  chemical  basis  of  the  cell,  it 
is  natural  to  devote  attention  in  the  first  place  to  this  food  principle. 

574 


NUTRITION    AND    (iki)\\  I'll 


.".t; 


In  tlic  pioneer  investigations,  studies  on  the  nitrogen  balance  in  young 

animals  yielded  results  from  which  it  was  concluded  that  the  conditions 
for  the  disintegration  of  protein  arc  less  developed  in  young  animals 
than  in  adults,  so  that  the  growing  organs  rapidly  withdraw  circulating 
protein  and  build  it  into  tissue  protein. 

In  consideration  of  the  accumulation  of  data  extending  over  several 
de.-ades,  Rubner  denied  these  conclusions,  and  showed  that  the  diet  of 
the  growing  infant  is  by  no  means  relatively  rich  in  protein.  He  con- 
cluded that  "growth  is  not  proportional  to  the  quantity  of  protein  in  the 
diet."  Important  though  this  pioneer  work  may  have  been  in  the  de- 
velopment of  our  present-day  conception,  the  viewpoint  of  the  men  who 
carried  it  out  was  very  much  narrowed  on  account  of  the  paucity  of 
knowledge  concerning  the  structure  of  the  protein  molecule.  No  allow- 
ance Mas  made  for  the  fact,  which  has  recently  been  firmly  established, 
that  the  protein  molecule  may  vary  extremely  in  regard  to  the  units 
of  which  it  is  composed,  and  that  the  growing  tissues  may  demand,  not 
so  much  an  abundance  of  protein  as  such,  but  rather  a  proper  supply  of 
all  the  building  stones  which  are  required  for  growth   (Mendel). 

Quantitative  Comparison  of  Amino  Acids  Obtained  by  Hydrolysis  of  Prot  :ins 
(Compiled  by  T.  B.  Osborne,  1914)  t 


oval- 

OX 

CAS3IN 

bumin 

GLIADIN 

ZEIN 

EDESTIN 

legt:min 

MUSCLE 

( rlycoeoll 

0.00 

0.00 

0.00 

0.00 

3.80 

0.38 

4.0 

Alanine 

1.50 

2.22 

2.00 

13.39 

3.60 

2.08 

8.1 

Valine 

7.20 

2.50 

3.34 

1.88 

6.20 

? 

2.0 

Leucine 

9.35 

10.71 

6.62 

19.55 

14.50 

8.00 

14.3 

Proline 

6.70 

3.56 

13.22 

9.04 

4.10 

3.22 

8.0 

Phenylalanine 

3.20 

5.07 

2.35 

6.55 

3.09 

3.75 

4.5 

Glutaminic  acid 

15.55 

9.10 

43.66 

26.17 

18.74 

13.80 

10.6 

Aspartic  acid 

1.39 

2.20 

0.58 

1.71 

4.50 

5.30 

22.3 

Serine 

0.50 

? 

0.13 

1.02 

0.33 

0.53 

? 

Tyrosine 

4.50 

1.77 

1.61 

3.55 

2.13 

].55 

4.4 

( Vstine 

? 

? 

0.45 

? 

1.00 

? 

? 

Histidine 

2.50 

1.71 

1.84 

0.82 

2.19 

2.42 

4.5 

Arginine 

3.81 

4.91 

2.84 

1.55 

14.17 

10.12 

11.5 

Lysine 

5.95 

3.76 

0.93 

0.00 

1.65 

4.29 

7.6 

Tryptophane,  about    1.50 

present 

1.00 

0.00 

present 

present 

present 

Ammonia 

1.61 

65.-49 

1.34 

4S.S5 

5.22 

85.68 

3.64 

88.87 

3.28 

82.28 

1.99 

57.43 

1.07 

102.87 

*These    analyses    are    combinations    of    what    appear    to    be    the    best    determinations    of    various 
chemists. 

tThe   figures   for   the   more   recent   analyses   of  gliadn   are   inserted. 


From  the  accompanying  table  giving  the  percentage  of  the  various 
amino  acids,  etc.,  present  in  certain  proteins,  it  will  be  evident  that  there 
are  very  marked  variations  in  the  units  of  which  different  proteins  are 
composed.    If  any  one  of  these  units  should  be  essential  for  growth  and 


576 


METABOLISM 


the  organism  be  unable  to  manufacture  the  missing  unit  for  itself,  it 
is  clear  that  growth  could  not  proceed  however  much  protein  not  contain- 
ing the  necessary  unit  we  might  feed  to  the  animal.  It  is  an  application 
of  the  law  of  the  minimum,  and  is  analogous  with  the  failure  of  growth 
which  has  long  been  known  to  ensue  when  certain  inorganic  substances 
are  withheld  from  the  growing  animal.  A  diet  might  be  perfectly  bal- 
anced as  judged  by  comparison  of  the  nitrogen  intake  and  output,  and 
yet  if  it  should  fail  to  contain  even  one  of  the  essential  units  and  the 
organism  should  be  incapable  of  supplying  this  unit,  then  would  the 
diet  be  inadequate  for  growth. 

These  important  facts  are  the  outcome  of  modern  work,  and  they 
have  been  established  by  observations  on  the  growth  of  young  animals 
fed  with  a  "basal  ration"  to  which  were  added  mixtures  of  amino  acids 


facrt  division  =  20 days 


Days 


Each  division  =  20 days. 


Fig.  183. — Curves  of  growth  of  rats  on  basal  rations  plus  the  various  proteins  indicated.  The 
normal  curve  may  be  taken  as  that  with  casein  (I).  (Adapted  from  Lafayette  B.  Mendel  and 
T.    B.   Osborne.) 

or  various  proteins  which  differ  considerably  from  one  another  in  the 
nature  of  the  units  entering  into  their  make-up.  In  such  experiments 
the  periods  during  which  growth  is  observed  must  be  prolonged,  since 
a  transient  increase  in  weight  might  depend  merely  on  repair  processes 
occurring  in  tissues  which  had  previously  for  some  reason  been  brought 
below  par. 

Among  the  most  important  observations  have  been  those  of  Lafayette  B. 
Mendel  and  T.  B.  Osborne8  and  of  MeCollum  and  his  collaborators.  The 
animals  chosen  for  Mendel  and  Osborne's  experiments  were  young  white 
rats.  Large  batches  of  these  animals  were  fed  on  a  basal  ration  consisting  of 
protein-free  milk  (containing  the  inorganic  salts,  the  sugars,  traces  of 
protein,    and   unknown   substances   having    an   important    influence    on 


NUTRITION    AND   CiROWTII 


577 


growth  vitamines?),  to  which  were  added  more  carbohydrate,  purified 
fat,  and  the  protein  whose  influence  on  growth  it  was  desired  to  study. 

The  same  diet  was  fed  a1  regular  intervals  to  a  given  batch  of  rats,  and 
the  weighl  of  each  ral  was  periodically  taken,  the  observation  being  pro- 
longed until  the  animals  grew  to  maturity  and  produced  young,  and  these 
again  grew  to  maturity,  reproduced,  and  so  on.  By  plotting  the  re- 
sults in  curves,  with  the  time  periods  along  the  abscissae  and  the  average 
weight  of  the  rats  of  each  batch  along  the  ordinates,  the  extent  of  the 
influence  of  a  given  diet  on  the  curve  of  growth  was  obtained.  A  normal 
curve  of  growth  is  shown  in  No.  1  of  Fig.  183.  It  was  obtained  from  re- 
sults secured  by   adding  liberal  amounts   of  casein  to   the   basal   diet. 


w 

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Days  Each  division  -20  days  Days  Each  division  -  20  days 

Fig.  1S4. — Curves  of  growth  of  rats  on  basal  rations  plus  the  proteins  indicated.  In  curve 
III  the  effect  of  the  addition  of  zein  to  an  inadequate  allowance  of  the!  perfect  protein,  lactalbumin, 
is  shown;  and  in  IV  the  effect  of  the  addition  of  cystine  to  a  deficient  casein  allowance.  (From 
Lafayette  B.  Mendel  and  T.  B.  Osborne.) 

Similar  curves  were  obtained  with  lactalbumin  of  milk  and  ovalbumin 
and  ovovitellin  of  egg.  Perhaps  the  most  interesting  substances  capable 
of  producing  the  normal  curve  of  growth  are  certain  of  the  proteins  that 
T.  B.  Osborne  has  succeeded  in  separating  in  crystalline  form  from 
vegetable  foodstuffs.  These  are  edestin  (hempseed),  globulin  (squash 
seed),  excelsin  (Brazil  nut),  glutelin  (maize),  globulin  (cottonseed), 
glutein  (wheat),  glycinin  (soy  bean),  cannabin  (hempseed). 

That  growth  proceeds  normally  with  any  one  of  these  proteins  when 
fed  abundantly  does  not,  however,  necessarily  indicate  that  each  con- 
tains in  adequate  proportion  all  of  the  necessary  units  to  meet  the  pro- 
tein demands  of  growing  tissues.  In  the  case  of  casein,  for  example, 
one  of  the  units,  namely,  glycocoll,  which  is  the  simplest   of  all  the 


578  METABOLISM 

amino  acids,  is  entirely  missing,  and  another,  cystine,  which  is  a  sul- 
phur-containing amino  acid,  is  present  only  in  small  amount.  The  ab- 
sence of  glycocoll,  however,  is  not  of  importance,  because  the  organism 
can  manufacture  it  for  itself  (see  page  630).  In  the  case  of  cystine, 
which  the  tissues  can  not  manufacture  themselves,  the  deficiency  has  to 
be  made  up  for  by  feeding  an  excess  of  casein  so  as  to  cover  the  needs 
of  the  tissues  for  this  amino  acid.  By  so  doing  a  superabundance  of 
most  of  the  other  units  will  be.  ingested,  and  this  superabundance  will 
entail  the  destruction  and  excretion  of  the  useless  amino  acids,  a  process, 
however,  which  is  conducted  in  such  a  way  as  to  permit  of  the  utilization, 
by  the  organism,  of  a  part  of  the  energy  which  the  cast-off  amino  acids 
contain  (see  page  667).     It  is,  therefore,  not  entirely  a  wasteful  process. 

When  the  supply  of  casein  is  limited,  on  the  other  hand,  the  curve 
of  growth  becomes  subnormal,  because  an  insufficient  supply  of  cystine 
is  thereby  offered  (Fig.  184).  Similar  results  have  been  obtained  in  the 
case  of  edestin,  a  protein  from  hempseed.  This  contains  an  insufficiency 
of  the  diamino  acid,  lysine.  Fed  in  abundance,  edestin  gave  a  normal 
curve  of  growth,  but  when  fed  in  insufficient  amount  the  curve  failed  to 
ascend  properly,  which,  however,  it  could  be  made  to  do  by  adding  some 
lysine  to  the  edestin. 

There  is  a  large  group  of  proteins  which  fail  to  permit  of  any  growth 
no  matter  in  what  amounts  they  may  be  added  to  the  basal  ration.  These 
include:  legumelin  (soy  bean),  vignin  (vetch),  gliadin  (wheat  or  rye), 
legumin  (pea),  legumin  (vetch),  hordein  (barley),  conglutin  (lupine), 
gelatine  (horn),  zein  (maize),  phaseolin  (kidney  bean).  The  adequacy 
to  maintain  growth  of  any  of  these  pure  proteins  varies  according  to 
the  deficiency  in  their  amino  acids.  In  the  case  of  gliadin  of  wheat  or 
rye,  glycocoll  is  lacking,  and  lysine  is  present  only  in  small  amount  (see 
table).  The  absence  of  glycocoll  can  not,  however,  as  we  have  already 
seen  in  the  case  of  casein,  explain  the  inadequacy  of  gliadin  as  a  foodstuff 
for  growth  (Curve  II  in  Fig.  183) .  It  must  be  the  lysine  that  is  at  fault.  A 
still  more  deficient  protein  is  the  zein  of  maize.  With  this  as  the  only 
protein  added  to  the  basal  diet,  the  curve  of  growth  actually  descends 
(Curve  III  of  Fig.  183),  thus  indicating  that  the  animal  is  starving  and 
must  soon  succumb.  The  missing  units  in  this  protein  are  glycocoll, 
lysine  and  tryptophane  (see  table  on  page  575),  and  it  is  very  signifi- 
cant that  if  the  latter  two  amino  acids  are  supplied  along  with  zein,  an 
almost  normal  curve  of  growth  will  result.  Some  improvement  can 
even  be  brought  about  by  giving  tryptophane  alone ;  that  is  to  say,  the 
curve  assumes  a  horizontal  line  instead  of  descending,  indicating  that, 
although  inadequate  for  growth,  the  diet  is  now  sufficient  for  the  main- 
tenance of  life. 


NUTRITION    AND    GROWTH 


579 


The  important  fact  demonstrated  by  these  experiments,  is  that  cer- 
tain diets  are  adequate  for  the  maintenance  of  life  although  they  are 
inadequate  for  growth.  In  conformity  with  this  conclusion,  it  was  found 
when  young  white  rats  were  Eed  with  gliadin  alone  for  periods  of  time  ex- 


Fig  185 —Photographs  of  rats  of  same  brood  on  perfect  diet  (uppermost  picture) ;  on  a  main- 
tenance diet  but  inadequate  for  growth  (middle  picture);  and  on  a  diet  that  was  inadequate  both 
for    maintenance   and   growth.      (From   Mendel   and    Osborne.) 

ceeding  those  in  which  they  should  have  become  full  grown,  that 
they  remained  in  an  ungrown  stunted  condition.  The  capacity  to  grow 
had  not,  however,  been  lost,  for  when  the  gliadin  was  replaced  by  milk, 
the  animals  resumed  growth  at  a  very  great  rate.    The  capacity  to  grow 


580  METABOLISM 

had  only  been  inhibited  by  the  inadequate  diet,  and  there  was  nothing 
really  abnormal  about  the  stunted  animals.  For  example,  the  reproduc- 
tive function  developed  normally,  as  was  shown  in  the  case  of  a  young 
female  rat  which,  after  being  fed  with  gliadin  as  the  sole  protein  sup- 
ply for  154  days,  was  mated  and  produced  four  young.  Although  the 
mother  was  still  maintained  on  the  gliadin  diet,  the  young  rats  pre- 
sented normal  growth,  for  they  were  living  on  the  milk  supplied  by  the 
mother,  and  this  milk,  because  it  contained  either  casein  or  some  other 
necessary  accessory  factor  (vide  infra),  was  an  adequate  food. 

After  removal  from  the  mother,  three  of  these  rats  were  fed  on  an  arti- 
ficial diet  of  casein,  edestin  and  the  basal  ration,  and  continued  the  nor- 
mal course  of  growth,  but  when  one  of  them  was  placed  on  the  gliadin 
food  mixture  it  immediately  failed  to  grow  properly.  It  would  appear 
from  these  experiments  that,  of  the  two  amino  acids  that  are  missing  or 
deficient  in  gliadin — namely,  glycocoll  and  lysine — it  must  be  the  lysine 
that  is  essential  for  growth.  This  very  important  conclusion  was  fully 
corroborated  by  "finding  that,  in  young  rats  stunted  by  previous  gliadin 
feeding,  growth  immediately  started  when  lysine  was  added  to  the  diet 
and  ceased  again  when  the  lysine  was  removed,  and  so  on,  the  experi- 
ments being  often  repeated  in  various  modifications.  Mendel  and  Os- 
borne call  attention  to  the  relatively  high  percentage  of  lysine  in  all 
those  proteins  that  are  concerned  in  nature  with  the  growth  of  young 
animals;  thus,  it  is  present  in  large  amounts  in  casein,  lactalbumin  and 
egg  vi  tell  in. 

It  is  particularly  in  protein  of  vegetable  origin  that  indispensable  units 
are  likely  to  be  missing,  the  best  known  of  these  units  being  the  aromatic 
amino  acids,  tyrosine  and  tryptophane ;  the  diamino  acid,  lysine ;  and 
the  sulphur-containing  acid,  cystine.  Some  animal  proteins,  such  as 
gelatine,  also  fail  to  contain  aromatic  groups,  and  are  therefore  utterly 
inadequate  as  protein  foods. 

That  the  absence  of  one  or  two  units  should  render  a  protein  utterly 
incapable  of  maintaining  life  suggests  that  a  specific  role  may  be  taken 
by  certain  amino  acids  in  the  maintenance  of  nutritional  rhythm;  thus, 
they  may  be  necessary  for  the  elaboration  of  some  hormone  or  other  in- 
ternal secretion  essential  to  life,  such  as  epinephrine,  the  active  principle 
of  the  suprarenal  gland.  This  is  an  aromatic  substance  not  far  removed 
in  its  chemical  structure  from  tyrosine  (see  page  734).  It  is 
therefore  natural  to  suppose  that  the  absence  of  the  tryptophane  unit 
in  zein  is  the  reason  that  this  protein  is  incapable  of  maintaining  the  in- 
itial body  weight. 

In  attacking  the  problem  from  this  viewpoint,  Hopkins  and  Will  cock10 
made  observations  on  the  survival  period  of  young  mice;  that  is,  the 
period  during  which  the  animals  survived  when  fed  on  a  basal  diet 


NUTRITION    AMI   GROWTH  581 

mixed  either  with  zein  alone  or  with  zein  plus  Bmall  quantities  of  tryp- 
tophane. It  was  found  that,  with  zein  alone,  the  mice  were  unable  to 
maintain  growth;  they  lost  in  weight  and  died  in  from  about  a  week  to 
about  a  month.  Other  mice  fed  on  the  same  amount  of  basal  diet  and 
zein.  but  to  which  was  also  added  some  tryptophane,  although  they  did 
not  grow,  were  capable  of  maintaining  their  body  weight  and  lived  in 
some  instances  for  nearly  a  month  and  a  half.  There  were  other  indica- 
tions of  the  difference  in  the  efficiency  of  the  two  diets.  The  mice  fed 
on  the  zein  alone  were  very  inactive,  and  remained  for  a  considerable 
period  of  the  time  in  a  condition  of  torpor.  The  hair  was  ruffled,  the 
eyes  were  half  closed,  and  the  ears,  feet  and  tail  were  cold.  The  ani- 
mals, however,  gave  evidence  of  having  a  good  appetite.  On  the  other 
hand,  the  mice  to  which  tryptophane  was  also  given  manifested  a  strik- 
ingly different  behavior,  being  active  and  more  or  less  normal  until 
just  before  death.  That  both  groups  of  animals  failed  to  live  more  than 
forty-four  or  forty-eight  days  is  probably  to  be  accounted  for  by  the 
absence  in  the  zein  of  the  other  unit,  lysine.  Had  this  been  added  along 
with  the  tryptophane  it  is  probable,  in  the  light  of  Mendel  and  Osborne's 
observations,  that  the  animals  would  have  survived  much  longer. 

To  supply  the  missing  unit,  besides  using  the  pure  amino  acid,  we 
may  employ  other  proteins  which  contain  the  required  amino  acid  (Curve 
III  of  Fig.  184).  That  mixtures  of  protein  foodstuffs  are  desirable  has  long 
been  apparent  to  those  who  have  studied  practical  dietetics.  We  must  com- 
bine the  unsuitable  protein  with  others  which,  although  in  themselves 
perhaps  also  unsuitable,  yet  furnish  us  with  a  mixture  which  contains  all 
the  essential  units  both  for  maintenance  and  growth.  As  Mendel  points 
out,  these  considerations  suggest  that  we  may  be  able  to  utilize  certain 
of  the  low  priced  protein  by-products  of  the  cereal,  meat  and  milk  in- 
dustries. The  test  of  the  adequacy  of  the  corrected  diet  must,  however, 
be  determined  by  experiments  of  the  type  which  we  have  just  described. 
It  is  probably  in  stock-raising  rather  than  in  connection  with  human  nu- 
trition that  these  facts  will  prove  of  practical  value;  for,  not  only  is  the  diet 
of  man  more  varied,  but  it  contains  animal  proteins  in  which  the  deficien- 
cies are  not  so  common. 

Most  important  work  of  this  character  is  being  conducted  by  McCol- 
lum  and  his  collaborators.12  It  would  take  us  beyond  the  confines  of 
this  book  to  discuss  the  results  in  detail,  but  it  may  be  mentioned  that 
they  have  shown  that,  since  the  adequacy  of  the  diet  depends  on  a 
multiplicity  of  factors  besides  the  ammo-acid  make-up  of  proteins, — 
some  of  which  Ave  shall  discuss  immediately, — very  extensive  observa- 
tions with  various  food  mixtures  must  be  conducted  over  long  periods 
of  time.  The  nutritive  values  of  the  common  cereals  added  to  a  stand- 
ard diet  that  had  brought  the  animals  (rats)  to  the  threshold  of  death, 


582  METABOLISM 

were  found  to  be  as  follows:  "With  cornmeal  there  was  immediate  recov- 
ery and  rapid  growth,  both  of  which  were  also  secured  in  considerable 
degree  by  wheat  embryo  and  entire  wheat  kernel;  with  rye  and  oats,  on 
the  other  hand,  there  was  little  if  any  improvement. 

Much  work  is,  of  course,  yet  to  be  done  before  we  can  determine  the 
exact  role  which  each  unit  plays  in  the  physiologic  development  of 
young  animals.  To  sum  up  what  we  already  know,  it  may  be  said  that 
glycocoll  is  not  essential,  since  it  can  be  manufactured  by  the  animal 
itself;  that  tryptophane  is  essential  for  maintenance,  probably  because 
it  is  required  for  the  production  of  certain  essential  hormones,  for  the 
make-up  of  which  in  its  absence  other  tissues  must  become  disintegrated, 
leading  therefore  to  a  diminution  in  body  weight ;  and  that  lysine  ap- 
pears to  be  essential  for  growth.  Tissues  can  be  maintained  without 
lysine,  but  they  can  not  grow,  for  the  slight  trace  which  most  food  con- 
tains of  this  important  amino  acid  may  be  sufficient  for  maintenance 
purposes,  but  utterly  inadequate  for  growth.  That  the  young  rats  in 
the  experiments  of  Mendel  grew  normally  while  living  on  milk  supplied 
by  the  stunted  mother  indicates  that  the  requisite  lysine  must  have  been 
produced  in  the  mother's  body. 

In  the  application  of  the  foregoing  principles  to  human  dietetics,  it 
is  undoubtedly  safe  to  follow  Bayliss's  advice  to  take  care  of  the  calo- 
ries and  allow  the  proteins  to  take  care  of  themselves.11  For  example, 
in  the  case  of  milk  the  deficiency  of  cystine  in  its  chief  protein,  casein, 
is  corrected  by  the  presence  of  lactalbumin,  which,  though  present  in 
only  small  amounts,  contains  sufficient  quantities  of  this  amino  acid  to 
meet  the  demands  of  the  growing  tissue. 

These  observations  on  maintenance  and  growth  suggest  very  interest- 
ing applications  in  connection  with  the  growth  of  tumors.  Is  it  possible 
that  we  might  retard  the  growth  of  tumors  by  a  diet  that  was  insufficient 
for  growth  while  sufficient  for  maintenance.  In  an  experiment  devised 
to  test  this  proposition  mice  were  fed  on  a  diet  of  starch,  lard,  lactose 
and  gluten  on  which  they  could  merely  maintain  existence  but  failed 
to  grow.  Some  of  these  rats  were  inoculated  with  a  rapidly  growing 
tumor  at  the  same  time  as  another  batch  of  mice  kept  on  normal  diet,  and 
it  was  found  that  the  tumor  grew  much  more  slowly  in  the  stunted  mice 
-than  in  the  others.  One  mouse,  for  example,  on  the  restricted  diet  had 
a-  scarcely  visible  tumor  52  days  after  the  inoculation.  When  this  mouse, 
however,  was  placed  on  a  normal  diet  of  bread,  milk,  etc.,  the  tumor 
immediately  began  to  grow  at  a  very  great  rate.13  Too  much  importance 
should  not  be  placed  on  this  experiment. 

We  shall  now  pass  on  to  consider  some. of  the  factors  besides  the  pro- 
tein content  which  have  an  important  bearing  on  dietetic  efficiency. 


CHAPTER  LXV 
NUTRITION  AND  GROWTH  (Cont'd) 

THE  RELATIONSHIP  OF  OTHER  FACTORS  THAN  PROTEINS 

The  Relationship  of  Carbohydrates. — As  we  have  seen  elseAvhere,  car- 
bohydrates are  almost  certainly  essential  for  normal  metabolism.  If  they 
are  not  given  with  the  food,  they  must  be  manufactured  out  of  protein  by 
the  organism  itself.  It  is  not  surprising,  therefore,  that  their  absence 
from  the  diet  of  growing  animals  should  lead  to  abnormality  in  the 
rate  of  growth.  Pediatrists  have  not  infrequently  insisted  that  one 
form  of  carbohydrate  is  more  advantageous  for  growth  than  another. 
This  no  doubt  in  the  main  is  true,  but  the  whole  question  of  adequacy 
probably  depends  on  the  digestibility  of  the  carbohydrate  and  not  upon 
its  essential  chemical  nature.  It  is  likely  that  the  only  carbohydrate 
required  by  the  tissues  is  glucose.  The  readiness  with  which  the  car- 
bohydrate of  the  food  becomes  converted  into  this  monosaccharide  is 
probably  the  only  determinant  of  its  efficiency  as  food  material. 

The  Relationship  of  Fats. — Although  fats  are  an  invariable  constit- 
uent of  practically  every  diet,  it  is  yet  a  debatable  question  as  to 
whether  they  are  essential  to  the  maintenance  of  a  healthy  normal 
organism.  Difficulties  standing  in  the  way  of  a  solution  of  this  problem 
are  that  it  is  not  only  technically  very  difficult  to  remove  fat  entirely 
from  the  common  foodstuffs,  but  also  that  the  simple  fats  are  usually 
associated  with  substances  having  similar  solubilities  and  physical 
properties:  namely,  the  lipoids,  phosphatides,  cholesterol,  pigments,  etc. 
Since  these  substances  are  present  in  practically  every  cell,  it  is  almost 
certain  that  they  can  be  manufactured  by  living  protoplasm.  Indeed, 
experimental  evidence  is  not  wanting  to  show  that  this  is  actually  the 
case.  Although  the  cell  can  manufacture  lipoids,  a  young  animal  can 
apparently  not  grow  when  these  substances,  as  well  as  simple  fat,  are 
entirely  absent  from  the  diet.  This  has  been  shown  by  feeding  young 
mice  on  a  diet  from  which  all  traces  of  fat  and  lipoids  had  been  removed 
by  extraction  with  alcohol  and  ether  (Stepp)14.  On  such  a  diet  the  mice 
lived  only  a  few  weeks.  They  could  be  kept  alive  much  longer  when 
some  of  the  alcohol-ether  extract  was  mixed  with  the  diet,  but  not  so 
when  neutral  fat  instead  of  the  alcohol-ether  extract  was  added.     The 

583 


584  M  ETABOLISM 

addition  of  the  ash  of  the  lipoid  extract  failed  to  maintain  the  mice,  so 
that  the  lacking  substance  could  not  be  inorganic  in  nature. 

More  recent  and  extended  observations,  however,  have  shown  that  neutral 
fat  is  also  necessary  for  the  adequate  and  continued  growth  of  the 
animal.  For  a  period  of  two  months  or  so  an  animal  may,  as  we  have 
seen  from  Osborne  and  Mendel's  experiments,  grow  in  apparently  nor- 
mal fashion  on  an  artificial  fat-  and  lipoid-free  diet  composed  of  casein, 
carbohydrate  and  inorganic  salts,  but  sooner  or  later  the  great  majority 
of  these  animals  begin  to  show  failure  of  adequate  growth.  The  in- 
adequately growing  animals  often  manifest  indications  of  malnutrition 
other  than  the  failure  to  increase  in  weight;  for  example,  inflammation 
of  eyes,  roughening  of  the  fur,  etc.  When  certain  fats  are  added  to 
the  inadequate  diet,  normal  growth  is  immediately  resumed.  Fats  pro- 
ducing this  normal  growth  are  such  as  butter  fat,  or  the  fat  extracted 
from  egg  yolk,  or  cod-liver  oil,  added  to  the  extent  of  5  per  cent  of  the 
ration.  On  the  other  hand,  vegetable  oils,  such  as  olive  oil  or  almond 
oil,  are  inefficient  in  promoting  growth.  That  all  oils  or  fats  do  not 
suffice  to  produce  growth,  and  that  one  dose  of  an  adequate  oil  or  fat  may 
be  sufficient  to  stimulate  it,  indicate  that  something  other  than  the  mere 
presence  of  the  comparatively  simple  fat  molecule — that  is,  some  acces- 
sory material — must  be  the  agency  responsible  for  the   growth. 

This  conclusion  is  further  supported  by  the  interesting  observation  of 
McCollum  and  Davis  that  vegetable  oils  can  be  rendered  efficient  for 
growth  by  shaking  them  with  a  solution  of  soap  prepared  by  com- 
pletely saponifying  butter  fat  with  potassium  hydroxide  in  the  absence 
of  water. 

ACCESSORY  FOOD  FACTORS,  VTTAMINES 

In  searching  for  the  nature  of  the  accessory  food  factors,  the  im- 
portant observations  which  have  been  made  in  recent  years  concerning 
the  so-called  vitamines  must  be  considered.  These  are  substances  essential 
in  the  diet  for  the  proper  maintenance  of  nutrition  in  adult  animals. 

The  existence  of  such  substances  was  suggested  by  observations  on 
the  disease  beriberi,  which  is  caused  by  exclusive  feeding  on  polished 
rice;  that  is,  on* rice  from  which  the  pericarp  had  been  removed  by  the 
process  of  polishing.  "When  patients  suffering  from  this  disease  were 
given  unpolished  rice,  the  symptoms  immediately  disappeared.  Further 
investigation  of  the  exact  nature  of  these  substances  was  greatly  facil- 
itated by  the  discovery  that  a  similar  condition  is  readily  induced  by 
feeding  fowls  on  polished  rice.  The  birds  develop  a  polyneuritis,  from 
which,  however,  they  very  promptly  recover  if  some  rice  polishings  or, 


\  i  TBITION    ami   GROWTH  585 

better  still,  an  extracl  of  rice  polishings,  is  added  to  the  polished  rice 
diet.  The  extracl  is  made  by  means  of  slightly  acid  91  per  cenl  alcohol, 
and  from  it  Funk  lias  succeeded  in  separating  a  substance  in  crystal- 
line form  apparently  related  to  the  pyrimidines,  which  it  will  be  re- 
membered  are  a  characteristic  constituent  of  the  nucleins.  Doses  as 
small  as  0.02  to  0.04  gm.  of  this  material  given  by  mouth  were  adequate 
to  cure  the  polyneuritis  of  fowls  in  from  six  to  twelve  hours;  indeed,  in 
some  eases  the  bird  seemed  quite  well  after  three  hours.  A  similar  sub- 
stance has  also  been  extracted  from  yeast,  milk,  brain  and  lime  juice, 
and  it  has  been  called,  for  want  of  a  better  name,  vitamine.15 

It  is  quite  likely  that  other  diseases,  such  as  scurvy,  may  also  be  due 
to  the  absence  of  some  vitamine  in  the  diet — some  substance,  namely, 
which  in  the  case  of  this  particular  disease  would  seem  to  be  absent  in 
preserved  food,  the  continued  taking  of  which  is  so  frequently  its  cause. 
Fresh  fruit  and  other  foods  added  even  in  small  amounts  to  such  a  diet 
would  appear  to  supply  the  necessary  vitamine. 

It  is  not  the  higher  animals  alone  that  suffer  from  the  want  of  some 
such  substance  as  vitamine.  It  has  been  shown,  for  example,  that,  when 
a  normal  artificial  culture  medium  is  inoculated  with  yeast  in  very 
small  amounts,  it  fails  to  grow,  whereas  the  same  quantity  will  grow 
luxuriantly  in  a  medium  to  which  sterilized  beer  wort  has  been  added. 
Vitamine  is  not  of  the  nature  of  a  ferment,  since  it  Avithstands  heating 
to  120°  C.  for  more  than  an  hour.  The  addition  of  yeast  to  dietaries 
that  are  deficient  in  vitamines  is  an  excellent  corrective. 

Returning  now  to  the  accessory  substances  that  seem  to  be  adherent 
to  certain  forms  of  fat,  Ave  see  at  once  that  they  can  not  be  exactly 
the  same  as  the  so-called  vitamine  of  Funk,  for  they  contain  no  nitrogen. 
There  are,  therefore,  probably  two  accessory  factors  concerned  in  ade- 
quate growth.  One  of  these  must  be  present  in  the  protein-free  milk 
which  serves  as  a  constituent  of  the  basal  diet  used  in  Osborne  and 
Mendel's  experiments,  for  Ave  have  seen  that  animals  Avill  grow  on  this 
for  a  certain  period,  provided  the  proper  amino  acids  are  present. 
Later,  hoAvever,  they  pass  into  a  state  where  there  is  no  groAvth  but 
adequate  maintenance.  If  now  the  other  accessory  factor  is  added,  as, 
for  example,  butter  fat  or  a  small  amount  of  milk  itself  (i.  e.,  in  place 
of  protein-free  milk),  then  growth  will  be  resumed  at  its  normal  rate. 
"Either  of  the  determinants  may  become  curative.  Both  are  essential 
for  groAvth  when  the  body  store  of  them  becomes  depleted."  McCollum 
suggests  that  these  accessory  factors  should  at  present  be  called  the 
"fat-soluble  A"  and  "Avater-soluble  B."  The  latter  is  present  in  yeast 
cells,  in  fat-free  milk,  and  in  many  other  animal  foods,  and  is  probably 
the  same  as  Funk's  vitamine.     The  former  is  soluble  in  the  fat  solvents, 


586  METABOLISM 

being  present  in  most  animal  fats,  but  not  in  all;  for  example,  it  is 
absent  from  the  fat  surrounding  the  pig's  heart.  By  using  such  a 
nomenclature  it  is  recognized  that  the  subject  is  as  yet  only  in  an  early 
state  of  development. 

We  may  sum  up  the  main  facts  of  this  chapter  by  stating  that  growth 
and  maintenance  are  more  than  a  mere  problem  of  energy  supply. 
Granted  that  this  is  sufficient,  we  must  also  have  a  suitable  admixture  of 
building  units  of  protein  and  the  presence  of  extremely  small  quantities1 
of  some  unknown  accessory  substances.  These  are  present  in  some  natural 
foods  but  not  in  others,  and  some  are  soluble  in  water  and  others  in  fats. 
They  are  found,  for  example,  in  animal  fats  but  not  in  those  of  vegetable 
origin.  Both  fat-  and  water-soluble  factors  are  present  in  large  quanti- 
ties in  milk. 

Both  accessory  food  factors  are  necessary,  as  is  illustrated  in  the  fol- 
lowing summary  of  experiments  from  Dusk's  "Science  of  Nutrition," 
(third  edition). 

Purified  protein  +  carbohydrate  +  vegetable  fat  +  inorganic  salts  =  no  growth. 
"  "        -f  "  -f- butter  fat        4-       "  "     =no  growth. 

"  "        +  "  + vegetable  fat  4-       "  "      +vitamines   (accessory 

factor  B)  =  no  growth. 
"  "        +  "  +  butter  fat        +       "  "     +  vitamines  =  growth. 

The  Relationship  of  Inorganic  Salts. — Inorganic  salts  ate  also  an  es- 
sential ingredient  of  the  diet.  McCollum  found  that  young  animals  soon 
ceased  to  grow  when  fed  on  a  diet  of  corn  and  purified  casein,  but  that 
rapid  growth  returned  when  a  suitable  salt  mixture  was  added.  Oats, 
wheat,  and  beans  have  also  been  shown  to  require  some  adjustment  of  their 
ash  content  to  make  them  adequate  for  growth.  Most  of  the  animal  foods 
contain  in  themselves  sufficient  inorganic  material,  as  is  evidenced 
among  other  things  by  the  adequacy  of  milk  alone  as  diet  for  growing 
animals  and  the  abhorrence  of  salt  that  is  shown  by  strictly  carnivorous 
animals.  In  the  usual  mixed  diet  of  man  there  is  almost  always  enough 
inorganic  material,  the  salt  Avhieh  he  adds  being  largely  for  seasoning 
purposes.  When  a  preponderance  of  vegetable  food  is  taken,  however, 
the  salt  comes  to  have  a  real  dietetic  value. 

The  practical  application  of  the  results  of  these  numerous  and  at 
present  somewhat  bewildering  observations  to  the  nutrition  of  man, 
and  particularly  to  the  dietetic  treatment  of  disease,  is  undoubtedly 
very  great.  This  is  especially  so  in  infants  and  growing  children,  in 
whom  the  correction  of  some  slight  inadequacy  in  the  diet  may  have 
the  most  pronounced  results,  not  only  on  growth  and  nourishment,  but 
also  on  the  power  of  resistance  against  disease  and  infection.  The  bene- 
ficial influence  of  cod-liver  oil,  for  example,  may  depend  on  some  fat- 


NUTRITION    AND   GROWTH  587 

soluble  accessory  food  factors,  while  the  miraculous  benefit  which 
scorbutic  children  derive  from  the  addition  of  the  juice  of  limes,  lemons, 
etc.,  to  the  food  is  undoubtedly  due  to  such  influences.  The  accumu- 
lating mass  of  evidence  as  to  the  faulty  nutrition  in  animals  fed  on 
single  kinds  of  food  that  fail  to  contain  both  kinds  of  food  factors 
emphasizes  the  necessity  in  the  dietetic  treatment  of  such  diseases  as 
diabetes,  nephritis,  etc.,  of  seeing  to  it  that  the  diet  is  sound,  not  only 
in  calories,  protein  content,  and  palatability,  but  also  with  regard  to 
the  presence  of  accessory  food  factors. 


CHAPTER  LXVI 

DIETETICS 

THE  CALORIE  REQUIREMENT 

In  the  application  of  the  important  facts  that  have  been  reviewed  in 
the  preceding  chapters  to  the  science  of  dietetics,  the  question  arises  as 
to  how  we  may  determine  with  scientific  accuracy  just  exactly  how  much 
food  should  be  taken  under  varying  conditions  of  bodily  activity.  In  a 
general  way,  we  know  that  the  amount  of  food  that  we  require  to  take 
is  proportional  to  the  nature  and  amount  of  bodily  .exercise  that  is 
being  performed  at  the  time ;  and  that,  if  the  food  supply  is  inadequate, 
the  work  before  long  will  fall  off  not  only  in  quantity  but  in  quality  as 
well.  "Horses  (also  men)  -work  best  when  they  are  well  fed,  and  feed 
best  Avhen  they  are  well  worked,"  is  an  old  adage  and  one  the  truth  of 
which  can  not  be  overestimated  in  the  consideration  of  all  questions  of 
dietary  requirements.  An  ill-fed  beggar  will  rather  suffer  from  the 
pain  and  misery  of  starvation  than  attempt  to  perform  a  piece  of  work 
that  the  well-meaning  housewife  bargains  should  be  done  before  she 
gives  him  a  meal.  The  spirit  may  be  willing  but  the  flesh  is  weak.  If  he 
could  be  trusted,  he  should  be  fed  first  and  worked  afterwards.  Besides 
the  amount  of  work,  two  other  factors  are  well  known  to  influence  the 
demand  for  food — namely,  growth  and  climate.  A  young,  growing  boy 
will  often  demand  as  much  if  not  more  food  than  would  appear  to  be 
his  proper  share,  from  a  comparison  of  his  body  weight  with  that  of 
his  seniors;  and,  other  things  being  equal,  it  is  well  known  that  we  are 
inclined  to  eat  much  more  heartily  of  food  during  the  cold  days  of 
winter  than  during  the  sultry  days  of  July  and  August. 

That  we  know  these  facts  in  a  general  way,  indicates  that  the  first 
step  to  take  in  the  exact  determination  of  dietetic  requirements  is  to 
find  out  how  much  energy  the  body  expends  under  varying  conditions 
of  activity.  This,  as  we  have  seen,  may  be  done  by  having  the  person 
live  for  some  time  in  a  respiration  calorimeter,  so  that  we  may  measure 
the  calorie  output.  To  the  conclusions  drawn  from  results  of  observa- 
tions made  under  such  artificial  and  unusual  conditions  of  living,  the 
objection  might,  however,  quite  justly  be  raised  that  they  need  not 
apply  to  persons  going  about  their  ordinary  routine  of  life.     To  meet 

588 


DIETETICS  589 

this  objection  another  method,  which  we  may  call  the  statistical,  is  avail- 
able. It  consists  in  baking  the  average  diel  <>l'  a  Large  number  of  indi- 
viduals and  comparing  the  calorie  value  with  the  average  amount  and 
type  of  work  thai  they  are  meanwhile  called  upon  to  perform,  and  can 
besl  be  used  where  the  diet  is  accurately  known,  as  in  public  institu- 
tions, the  army,  the  navy,  etc.  The  total  food  supplied  is  then  divided 
by  the  number  of  individuals,  this  giving  the  per  capita  consumption. 
Obviously  some  get  more  than  others,  hut  when  a  sufficient  numher  of 
individuals  is  included,  such  errors  become  eliminated  by  the  law  of 
averages. 

The  reliability  of  this  method  is  testified  to  by  the  remarkable  corre- 
spondence in  the  calorie  value  of  the  food  consumed  by  farmers  in  widely 
different  communities: 

Calories 

Farmers   in    Connecticut 3,4 1 0 

"        "     Vermont     3,635 

"       "    New  York 3,785 

"       "    Italy 3,565 

"        "     Finland    3,474 

Average 3,551* 

*Lusk:     The   Fundamental   Basis  of  Nutrition. 

The  average  inhabitant  of  various  cities: 

London    2.665 

Paris 2,903 

Munich    3,014 

Konigsberg 2,394** 

**Ruhner. 

Individuals  in  different  callings: 

Farmers'   families    (U.S.A.) 3.560 

Mechanics'  families   (U.S.A.) 3,605 

Professional  men's  families   (U.S.A.) 3,530 

Army   (U.S.A.) 3,851 

Navy    (U.S.A.)    4,998t  . 

tAtwa'er. 

In  general,   it   is  usually  computed  that   a  man 
weighing  70  kg.  requires  in  calories: 

2,500  for  a  sedentary  life, 
3,000  for  light  muscular  work, 
3.500  for  medium  muscular  work, 
4,000  and  upwards  for  very  hard  toil.} 
IMcKillop. 

These  figures  apply  to  the  average  man,  but  in  calculating  the  calorie 
requirements  of  a  family  or  a  community  we  must  make  allowance  for 
the  lesser  requirements  of  women  and  children.  Several  dietitians  have 
compiled  tables  showing  how  many  calories  are  expended  according  to 
age  and  sex,  and  the  German  authorities  have  recently  taken  these  figures 
and  from  them  calculated  a  generalized  mean,  which  shows  in  comparison 


590  METABOLISM 

with  men  the  percentage  that  should  be  allowed  for  women  and  children. 
The  figures  are  as  follows: 

Man     100 

Woman   83 

Boy  over   16 92 

Bov  14-16 81 

Girl   14-16    74 

Child   10-13    64 

Child  6-9    49 

Child  2-5    36 

Child  under  2 23 

In  calculating  the  calorie  requirement  of  the  population  as  a  whole, 
the  necessity  of  making  allowance  for  the  varying  needs  of  men,  women, 
and  children  would  obviously  make  the  calculations  far  too  complicated 
for  practical  purposes.  It  is  necessary  to  have  a  factor  by  which  we 
may  multiply  the  total  population  in  order  to  determine  its  "man  value." 
This  factor  is  based  on  the  relative  proportion  of  men  to  women  and 
children,  and  it  amounts  very  nearly  to  0.75,  i.  e.,  three-quarters  of  the 
total  population  gives  "the  man  value."  Knowing  the  total  population, 
say,  of  a  city,  we  must  therefore  multiply  this  by  0.75  in  order  to  ascer- 
tain for  how  many  men  doing  moderate  muscular  work  (3000  C.)  food 
has  to  be  provided. 

THE  PROTEIN  REQUIREMENT 

The  facts  considered  in  the  previous  two  chapters  lead  to  the  question: 
To  what  extent  may  the  proportion  of  protein  in  the  diet  be  reduced 
with  safety?  It  is  evident  that  there  must  be  a  minimum  below  which 
every  one  of  the  necessary  building  materials  of  protein  could  not  be 
supplied  in  adequate  amount  to  reconstruct  the  worn-out  tissue  protein. 

The  extent  to  which  the  protein  content  of  the  diet  of  man  can  be 
lowered  with  safety  depends  on  several  factors,  of  which  the  most  im- 
portant are:  first,  the  nature  of  the  protein;  second,  the  number  of  non- 
protein calories ;  and  third,  the  extent  of  tissue  activity.  Where  so  many 
factors  must  be  taken  into  consideration,  the  only  method  by  which  the 
actual  minimum  can  be  determined  consists  in  what  may  be  called  "cut 
and  try  experiments."  Of  the  many  investigations  of  such  a  nature, 
probably  the  best  one  for  us  to  consider,  is  that  recently  published  from 
the  Nutrition  Laboratory  of  Copenhagen.  The  subject,  an  intelligent 
laboratory  servant,  lived  a  perfectly  normal  and  active  life  for  a  period 
of  five  months  on  a  diet  of  potatoes  cooked  with  margarine  and  a  little 
onion,  and  containing  4000  C,  with  a  total  protein  content  of  29  grams. 
During  another  period  he  did  outdoor  work  as  a  mason  and  laborer,  and 
took  5000  C.  daily,  and  35  grams  of  protein. 


DIETETICS  591 

It  is  important  to  contrast  these  results  with  the  following  based  on 
municipal  statistics  of  gross  consumption. 

Municipal  Food  Statistics 


PROTEIN 

FAT 

CARBOHYDR 

ATKS 

CALORIES 

gm. 

gm. 

gm. 

Konigsberg 

84 

31 

M  1 

2394 

Munich 

96 

65 

492 

301  1 

Paris 

98 

64 

465 

290.°, 

London 

98 

60 

416 

2665 

It  is  certain  that  man  can  lead  a  normal  existence  and  remain  in  good 
health  on  very  much  less  protein  than  the  100  grams  which  statistical 
studies  show  to  be  the  amount  he  actually  takes.  This  discrepancy  be- 
tween the  amount  which  experiment  demonstrates  to  be  adequate  and 
that  which  habit  and  custom  demand,  raises  the  question  as  to  whether, 
after  all,  our  instincts  may  not  have  erred  and  so  made  us  unnecessarily 
extravagant  in  our  protein  intake.  It  has  been  suggested  that  such  pro- 
tein extravagance  will  in  various  ways  have  a  deleterious  effect  on  the 
organism ;  thus,  that  the  excretory  organs,  such  as  the  kidneys,  will  be 
overtaxed  in  eliminating  the  unused  amino  acids,  that  the  constant  pres- 
ence of  these  bodies  in  excess  in  the  blood  will  cause  degeneration  and 
sluggish  metabolism,  and  that  the  excess  protein  in  the  intestine  will 
lead  to  the  production  of  ptomaines,  whose  subsequent  absorption  into 
the  blood  will  cause  toxemic  symptoms. 

Important  support  to  such  views  appeared  to  be  supplied  some  dozen 
years  ago  by  Chittenden,  who  was  able  to  show  that  he  himself  and  many 
other  persons  doing  different  kinds  of  work  could  be  supported  on  daily 
amounts  of  protein  that  were  not  more  than  from  one-third  to  one-half 
of  the  amount  usually  taken.  Xot  only  so,  but  it  was  averred  that  dis- 
tinct improvement  was  experienced  in  the  general  sense  of  well-being 
and  of  mental  efficiency  as  a  result  of  the  lesser  protein  consumption. 

Taking  these  results  as  a  whole,  it  is  quite  clear  that  man  can  get 
along  under  ordinary  conditions  with  much  less  protein  than  he  usually 
takes;  but  that  really  proves  nothing,  for  the  question  is  not  can  he  but 
should  he,  so  deprive  himself?  Are  instinct  and  custom  wrong  and  is 
Chittenden  right  ?  That  is  the  question.  To  answer  it  many  studies  have 
been  made  of  the  condition  of  peoples  who  for  economic  or  other  rea- 
sons are  compelled  to  live  on  less  protein  than  the  average.  Are  these 
people  healthier,  less  prone  to  infections  and  degenerative  diseases,  and 
more  efficient  mentally  than  others?  In  such  studies  great  care  must  be 
exercised  to  see  that  conditions  other  than  diet,  such  as  climate,  exercise, 
etc.,  are  properly  allowed  for.  It  would  not  be  fair,  for  example,  to 
compare  the  mental  and  bodily  condition  of  peoples  living  in  the  tropics 


502  METABOLISM 

and  who  take  comparatively  little  protein,  with  those  living  in  temperate 
zones,  "who  consume  much  more.  After  discounting  all  of  these  other 
factors,  it  has  been  quite  clearly  shown  that,  when  the  protein  allowance 
is  matt  rially  reduced,  the  people  as  a  whole  are  less  robust,  mentally  in- 
ferior, and,  instead  of  being  less  prone  to  the  very  diseases  which  are 
usually  supposed  to  be  due  to  overloading  of  the  organism  with  useless 
excretory  products,  are  more  liable  to  suffer  from  them. 

That  a  decided  reduction  in  protein  weakens  the  defense  of  the  organ- 
ism against  infection  is  probably  due  to  the  fact  that  the  fluids  of  the 
body  normally  contain  a  great  variety  of  so-called  antibodies — that  is, 
of  highly  complex  substances  that  are  largely  protein  in  nature.  When 
bacteria,  or  the  poisons  produced  by  them,  enter  the  bo-dy,  they  are  met 
by  one  or  more  of  these  defense  substances  and  destroyed  or  neutralized. 
Now  it  is  clear  that  there  should  always  be  a  surplus  of  protein-building 
materials  from  which  the  antibodies  may  be  constructed.  Such  an  excess 
will  constitute  a  "factor  of  safety"  against  disease.  And  there  are  fac- 
tors of  safety  of  another  nature  to  be  provided  for,  two  of  which  we  are 
in  a  position  to  appreciate.  In  the  first  place,  there  must  always  be  an 
adequate  supply  of  tryptophane,  of  lysine,  and  of  cystine,  not  only  to 
meet  the  bare  necessities  of  the  protein  constructive  processes  that  go  on 
under  normal  conditions,  but  also  to  make  good  the  larger  amount  of 
protein  wear  and  tear  that  greater  degrees  of  tissue  activity  will  entail. 
Although  moderate  muscular  exercise  does  not  appear  to  cause  any  im- 
mediate consumption  of  protein  (carbohydrate  and,  later,  fat  being  the 
fuel  material  used  to  produce  it),  yet  it  does  throw  a  greater  strain  on 
the  tissues  and  causes  a  greater  wear  and  tear  of  the  machinery,  and 
hence  a  demand  for  more  protein-building  material.  In  the  second  place, 
there  are  certain  of  the  internal  secretions  of  the  body,  such  as  epineph- 
rine (adrenaline),  that  are  essential  for  life,  and  as  crude  materials 
for  the  manufacture  of  which  certain  amino  acids  are  essential.  Tyro- 
sine is  one  of  these,  and  since  proteins,  as  Ave  haA*e  seen,  differ  from  one 
another  quite  considerably  in  the  amount  of  this  amino  acid  which  they 
contain,  it  is  advisable  to  provide  an  excess,  so  that  an  adequate  supply 
of  tyrosine  may  always  be  available. 

The  answer  to  one  of  the  most  important  practical  questions  in  die- 
tetics— namely,  "What  proportion  of  protein  should  the  diet  contain?" 
depends  on  these  scientific  principles.  The  source  of  the  protein  is  the 
important  thing.  With  animal  protein  there  is  no  doubt  that  we  could 
get  along  with  perfect  safety  by  taking  daily  not  more  than  50  or  60 
grams,  which  is  about  half  of  what  we  actually  consume.  If  the  protein 
is  of  vegetable  origin  and  part  of  it  of  the  first  quality,  as  wheat  and 
Indian  corn  preparations,  more  should  be  taken  so  as  to  allow  for  the 


DIETETICS  593 

deficiency  of  certain  amino  acids.     When  vegetable  proteins  of  the  sec- 

I  quality,  such  as  those  of  peas,  beans,  lentils,  etc.,  are  alone  available, 

much  larger  amounts  are  accessary.    Such  proteins  are  inadequate  in  the 

ease  of  growing  children   al    least,  and  even    in   adults   it    is  undoubtedly 
advisable  that  other  proteins  should  supplement  them. 

To  insure  safety,  there  fore,  it  is  almost  imperative  that  the  diet  should 
contain  proteins  of  various  sources.  If  .for  economic  reasons  the  main 
source  must  he  proteins  of  vegetable  origin,  then  some  animal  protein,  such 
as  is  contained  in  milk  or  meat  or  eggs,  should  be  added  to  at  least  one  of 
the  daily  meals.  When  peas  and  beans  are  mainly  depended  on  for  the 
protein  supply,  they  should  be  taken  either  with  milk  or  one  of  its  prep- 
arations, or  with  a  thick  gravy  or  sauce  made  from  meat  and  containing 
the  finely  minced  meat.  This  must  not  be  strained  off,  for  if  it  is,  the 
sauce  will  contain  only  the  meat  extractives  but  not  any  of  the  protein, 
which  is  coagulated  by  the  boiling  water.  Meat  extract,  in  other  words, 
contains  no  proteins;  it  is  not  a  food  but  merely  a  condiment  of  no  greater 
dietetic  value  than  tea  or  coffee. 

ACCESSORY  FOOD  FACTORS 

Little  need  be  added  to  what  has  already  been  said  regarding  this 
subject.  The  practical  point  to  be  remembered  is  that  there  are  at  least 
two  accessory  factors  concerned,  one  of  them  soluble  in  fat  and  present 
in  adequate  amount  in  butter  and  other  animal  fats  but  not  in  vegetable 
oils,  and  the  other  soluble  in  water  and  present  in  wheat,  vegetables, 
fruits,  etc.  Milk  contains  both  of  these  factors,  so  that  its  inclusion  in 
a  diet  is  a  safeguard  not  only  against  inadequacy  in  suitable  protein,  but 
also  against  the  absence  of  accessory  food  factors.  There  is  little  danger 
of  the  diet  being  inadequate  with  regard  to  food  factors  if  it  contains 
some  fruits  or  green  vegetables  or  unheated  fresh  milk.  The  food  fac- 
tors are  destroyed  by  prolonged  cooking. 

DIGESTIBILITY  AND  PALATABILITY 

We  have  seen  that  practical  dietetics  depends  on  several  factors,  the 
exact  relative  importance  of  which  can  not  perhaps  be  gauged  in  every 
case,  but  preparation  of  the  food  so  as  to  make  it  appetizing  must  un- 
doubtedly rank  high.  The  importance  of  good  cooking  will  now  be  ap- 
parent. It  is  the  act  of  making  food  appetizing  and  therefore  digestible. 
It  is  really  the  first  stage  in  digestion,  the  stage  that  we  can  control,  and 
one  therefore  to  which  much  attention  must  be  given,  especially  when  it 
becomes  necessary  to  make  attractive  articles  of  diet  ordinarily  considered 
common  and  cheap.     Most  people  can  cook  a  lamb  chop  so  as  to  make  it 


594  METABOLISM 

reasonably  appetizing,  but  few  can  take  the  cheaper  cuts  of  meat  and  con- 
vert them  into  cooked  dishes  that  are  as  popular  and  attractive.  And  there 
are  still  fewer  who  can  take  the  left-overs  and  trimmings  and  convert  them 
in  the  same  way.  This  is  the  real  art  of  cooking,  and  too  much  encourage- 
ment can  not  be  given  to  the  effort  which  our  cooking  experts  are  making 
to  show  people  how  these  things  can  be  done.  The  waste  of  good  food  in 
a  large  city  is  truly  appalling. 

Cooking  has  other  advantages  than  making  the  food  appetizing.  The 
heat  loosens  the  muscle  fibers  of  the  meat  so  that  it  is  more  readily 
masticated ;  it  destroys  microorganisms  and  parasites  in  the  meat ;  it  de- 
stroys antibodies  which  might  interfere  with  the  action  of  the  digestive 
ferments.  Thus,  untreated  raw  white  of  egg  is  not  digested  in  the  stom- 
ach because  it  contains  one  of  the  antibodies  which  prevent  the  pepsin 
from  acting  on  it;  but  boiled  egg  white,  if  properly  chewed,  can  be  di- 
gested, and  whipping  the  egg  white  into  a  foam  partly  destroys  the  in- 
hibiting substance. 

Before  concluding,  something  should  be  said  about  the  laxative  quali- 
ties of  food,  for  it  is  often  in  this  particular  alone  that  one  food  is  more 
satisfactory  than  another.  A  diet  of  meat,  milk,  eggs,  and  white  bread  is 
apt  to  be  unphysiologic  because  there  is  nothing  in  it  to  act  as  what  has 
been  called  intestinal  ballast;  that  is,  a  material  which  will  keep  the 
intestines  sufficiently  filled  to  stimulate  their  muscular  movements.  This 
ballast  is  best  furnished  in  the  shape  of  cellulose,  the  most  important 
constituent  of  green  food.  Peas,  beans,  cabbage,  salad,  and  many  fruits, 
especially  apples,  should  always  occupy  a  place  in  the  daily  menu.  An- 
other valuable  food  yielding  this  ballast  is  the  outer  grain  of  wheat,  oats, 
etc.  So  much  must  not  be  taken  as  to  produce  a  constant  intestinal 
irritation,  and  each  person  must  determine  for  himself  where  this  limit 
lies.  The  difference  among  various  breads  is  almost  entirely  in  the  de- 
gree to  which  they  supply  ballast. 

The  all-important  subject  of  food  economies  can  receive  no  attention 
here,  except  to  point  out  that  it  is  one  which  must  be  most  carefully  con- 
sidered in  the  solution  of  all  problems  of  dietetics.  An  admirable  ac- 
count of  the  subject  will  be  found  in  Graham  Lusk's. "Science  of  Nutri- 
tion" (third  edition)  and  in  McKillop's  "Food  Values."16 


CHAPTER  LXVII 

THE  METABOLISM  OF  PROTEIN 

Introductory.— The  older  physiologists  believed  that  the  protein  taken 
with  the  food  was  brought  into  a  soluble  condition  by  the  digestive  en- 
zymes, and  that  it  was  then  absorbed  into  the  blood  and  directly  incor- 
porated with  the  tissues.  The  discovery  of  the  enzymes  trypsin  and 
erepsin  and  of  free  amino  acids  in  the  gastrointestinal  contents  clearly 
showed  that  this  simple  theory  of  Liebig  could  not  be  correct.  It  was, 
furthermore,  found  that  when  an  excess  of  proteins  such  as  egg  albumin 
gains  entry  to  the  blood,  part  of  the  protein  appears  in  an  unchanged 
condition  in  the  urine ;  and  that  enzymes  capable  of  digesting  this  protein 
but  not  other  varieties  make  their  appearance  in  the  blood. 

After  the  injection  of  foreign  proteins  into  the  blood,  symptoms  of 
varying  severity  often  develop,  from  the  almost  instantaneous  death 
produced  by  snake  venom  to  the  slowly  developing  anaphylactic  reac- 
tions which  follow  the  injection  into  the  blood  of  many  proteins  chemi- 
cally indistinguishable  from  those  of  the  blood  serum  itself.  When  pro- 
tein is  taken  in  the  usual  amounts  by  mouth,  these  poisonous  reactions 
do  not  supervene,— even  snake  venom  is  harmless  when  swallowed—nor 
is  it  possible  during  digestion  of  a  protein  meal  to  detect  food  protein  in 
the  blood  by  means  of  the  precipitin  reaction.  Finally  it  was  discovered 
that  the  very  slow  intravenous  injection  of  completely  digested  flesh  did 
not  produce  on  the  part  of  the  body  any  of  the  reactions  that  injected 
protein  itself  produces,  indicating  that  perfect  assimilation  had  occurred. 
From  these  and  similar  observations  it  soon  became  clear  that  protein 
can  not  be  absorbed  as  such  from  the  alimentary  canal,  but  must  first  of 
all  be  completely  broken  down  into  the  amino  acids,  which  are  then  rebuilt 
into  the  protein  of  the  organism.  The  direct  evidence  for  this  important 
change  in  belief  concerning  protein  metabolism  has  been  gained  by  the 
discoveries  that:  (1)  nitrogen  equilibrium  can  be  maintained  in  animals 
fed  with  completely  digested  protein  mixtures;  and  (2)  amino  acids  can 
be  isolated  from  the  blood. 

The  experiments  of  the  first  group  consist,  in  principle,  in  breaking 
down  protein  until  there  is  no  longer  the  characteristic  biuret  test,  and 
then  feeding  this  digestion  mixture  to  animals  and  observing  them  from 
day  to  day,  using  as  criteria  of  their  nutritional  condition  the  body  weight 

595 


596  METABOLISM 

and  the  nitrogen  equilibrium.  (Page  571.)  It  has  been  shown  that  suc- 
cess in  maintaining  nutritional  efficiency  depends  partly  on  the  nature 
of  the  process  used  for  digesting  the  protein,  and  partly  on  the  presence 
or  absence  of  carbohydrate  in  the  digestion  mixture.  It  was  found 
that  acid  hydrolytic  products  failed  to  maintain  equilibrium,  and  it  was 
believed  that  this  was  owing  to  the  fact  that  the  acid  had  more  completely 
disrupted  the  protein  molecule,  and  had  left  no  polypeptides,  which,  it 
was  imagined,  remained  intact  during  enzyme  action  and  were  essential 
for  proper  protein  metabolism.  This  view  has  now  been  considerably 
altered,  since  it  has  been  shown  that  the  acid  actually  destroys  certain 
amino  acids  which  the  enzyme  leaves  intact.  The  amino  acid  particu- 
larly concerned  is  tryptophane.  Thus,  when  animals  were  fed  with  three 
diets,  consisting  of  (1)  fully  digested  casein,  (2)  fully  digested  casein 
from  which  the  tryptophane  had  been  removed,  and  (3)  fully  digested 
casein  from  which  the  tryptophane  had  been  removed  and  then  the 
proper  amount  of  pure  tryptophane  added,  it  was  found  that  nitrogen 
equilibrium  could  not  lie  maintained  on  the  second  diet,  which  contained 
no  tryptophane,  whereas  it  was  maintained  on  the  first  and  third  diets. 
That  this  explanation  is  correct  is  further  supported  by  the  fact  that, 
if  the  protein  is  only  partly  digested  by  acid — that  is,  not  digested 
enough  so  as  to  break  up  all  the  tryptophane — it  can  efficiently  maintain 
nitrogen  equilibrium. 

Regarding  the  necessity  for  carbohydrates,  it  is  possible  that  under 
certain  conditions  these  may  be  produced  from  the  protein  itself.  At 
least,  it  has  been  possible  for  Abderhalden,  who  has  done  a  large  share 
of  this  work,  to  maintain  an  animal  in  nitrogen  equilibrium  with  a  diet 
of  digestion  products  and  fat  containing  no  carbohydrate. 

These  results  obtained  in  different  classes  of  animals  have  also  been 
confirmed  for  the  human  subject.  A  boy  suffering  from  a  stricture  of  the 
esophagus,  when  fed  by  rectum  for  fifteen  days  with  digestion  products 
resulting  from  the  action  of  trypsin  and  erepsin  on  flesh,  gave  evidence 
of  nitrogen  retention. 

Concerning  the  second  type  of  evidence,  many  investigators  attempted 
to  separate  the  amino  acids  themselves  from  the  blood,  particularly  dur- 
ing the  digestion  of  a  large  amount  of  protein,  but  the  results  were  at 
first  entirely  negative  because  of  the  lack  of  methods  that  were  suffi- 
ciently delicate  to  make  it  possible  to  detect  the  slight  increase  that 
could  be  expected  even  when  a  maximum  absorption  of  nitrogen  had 
occurred.  The  very  large  flow  of  blood  through  the  portal  vein  causes 
such  extensive  dilution  of  any  substances  added  to  it  that  the  concentra- 
tion of  the  substance  in  an  isolated  sample  of  the  blood  can  be  only 
trivial. 


Till:    MKTAMOUSM    OF    I'ROTKIN  597 

To  account  for  the  indisputable  disappearance  of  the  amino  acids  from 
the  intestine  during  protein  digestion,  coupled  with  the  impossibility  of 
detecting  any  of  them  in  the  blood,  two  views  were  current  for  many 

years.  One  of  these  was  that  the  amino  acids  hecome  deaminated  (NIL 
group  split  up  as  NIT,)  by  the  intestinal  epithelium,  and  the  other,  that 
these  cells  are  endowed  with  the  power  of  reconstructing  the  amino  acids 
into  protein,  which  then  passes  into  the  blood.  Justification  for  the  de- 
amination  hypothesis  seemed  to  he  obtained  by  the  observation  that  there 
is  more  free  ammonia  in  the  blood  of  the  portal  vein  than  in  that  of  the 
systemic  circulation.  The  falsity  of  this  evidence  was,  however,  defi- 
nitely established  by  Polin  and  Denis,32  who  found  by  means  of  delicate 
quantitative  methods  for  the  estimation  of  ammonia  and  urea  in  the  blood 
that  the  amount  of  neither  of  these  substances  became  increased  in  the 
portal  blood  during  absorption  of  amino  acids  from  the  intestine.  They 
made  the  further  important  discovery  that  the  ammonia  in  the  portal 
blood  is  really  very  little  in  amount,  and  represents  that  absorbed  as 
such  from  the  intestinal  lumen,  where  it  is  produced  chiefly  by  the  action 
of  putrefactive  bacteria. 

Nor  could  any  evidence  be  obtained  in  favor  of  the  hypothesis  that 
the  absorbed  amino  acids  become  built  up  in  the  intestinal  epithelium 
into  proteins,  which  are  then  transformed  or  carried  away  by  the  blood. 
This  hypothesis  was  based  entirely  on  negative  findings,  and  had  there- 
fore to  be  dropped  when  discovery  was  made  of  the  actual  presence  of 
amino  acid  in  the  blood. 

This  brief  historical  survey  of  the  subject  brings  us  to  a  position  where 
Ave  may  proceed  to  discuss  the  present-day  teaching  regarding  protein 
metabolism.  Briefly  stated,  this  teaching  is  to  the  effect  that  the  protein 
molecule  is  broken  down  into  its  ultimate  building  stones,  the  amino  acids, 
by  the  digestive  enzymes  of  the  gastrointestinal  tract,  and  that  these  amino 
acids  are  absorbed  into  the  blooel,  by  ivhich  they  are  carried  to  the  various 
organs  and  tissues,  which  sift  out  the  amino  acids  and  use  those  of  thorn 
ivhich  they  require  for  the  reconstruction  of  their  broken-down  protein. 
The  amino  acids  not  required  for  the  process,  along  with  those  ivhich  may 
be  liberated  in  the  tissues  themselves  by  disintegration  of  tissue  proteins, 
are  then  split  into  two  portions,  one  represented  by  ammonia  and  the  other 
by  the  remainder  of  the  amino  acid  molecule.  The  former  is  excreted  as 
urea  and  the  latter  is  oxidized  to  produce  energy. 

CHEMISTRY  OF  PROTEIN 

Before  proceeding  to  discuss  the  evidence  upon  which  the  above  con- 
clusions depend,  it  will  be  necessary  to  consider  some  of  the  most  important 
facts  concerning  the  chemistry  of  the  protein  molecule.    We  shall  require 


598  METABOLISM 

this  information  not  only  to  understand  the  history  of  protein  in  the 
animal  body,  but  also  to  follow  intelligently  the  important  work  that 
has  already  been  discussed  concerning  the  relative  value  of  different 
proteins  as  food.  A  knowledge  of  protein  chemistry  has  come  to  be 
essential  in  practically  all  branches  of  medical  science. 

Proteins,  like  starches,  are  composed  of  numerous  smaller  molecules. 
In  the  case  of  starch  these  molecules  are  the  various  monosaccharides — 
glucose  (dextrose),  levulose  and  galactose;  in  the  case  of  proteins  they 
are  the  amino  acids.  The  breaking  apart  of  the  links  that  hold  the  mole- 
cules together  is  effected  in  both  cases  by  the  process  of  hydrolysis,  so 
called  because  of  the  fact  that  the  reaction  consists  in  the  taking  up  of  a 
molecule  of  water  at  each  of  the  places  where  the  chain  falls  apart.  This 
hydrolysis  may  be  effected  either  by  the  action  of  mineral  acids  or  alka- 
lies, or  by  enzymes,  the  only  difference  in  the  action  of  these  reagents 
being  that  in  the  former  case  the  breaking  apart  takes  place  more  or 
less  indiscriminately,  whereas  in  the  latter  it  proceeds  according  to  a 
definite  plan,  which  varies  somewhat  with  the  type  of  enzyme  employed. 
Just  as  a  chemical  knowledge  of  the  structure  of  sugar  or  monosac- 
charides is  the  basis  of  carbohydrate  chemistry,  so  is  that  of  the  amino 
acids  the  basis  of  protein  chemistry. 

Amino  Acids. — There  are,  so  far  as  known,  eighteen  different  amino 
acids  concerned  in  the  constitution  of  protein,  but  they  are  all  alike  in 
their  characteristic  structure.  The  most  striking  characteristic  depends 
on  the  presence  in  the  molecule  of:  (1)  an  amino  group  with  a  basicity 
comparable  to  that  of  ammonia,  and  (2)  an  acid  group  with  an  acidity 
comparable  to  that  of  acetic  acid.  Let  us  take  in  illustration  one  of  the 
simplest  fatty  acids — namely,  acetic.  It  has  the  formula  CH3COOH. 
The  COOH  group  is  called  carboxyl,  and  on  it  depend  the  acid  properties 
of  the  compound.  The  CH3  group  is  known  as  methyl,  and  the  amino 
group  (NH2)  is  attached  to  it  in  place  of  one  of  the  hydrogen  atoms,  thus 
giving  the  formula  CH2NH2COOH,  which  is  aminoacetic  acid  or  gly- 
cocoll.  If  we  take  the  next  higher  acid  of  the  fatty  acid  series,  having 
the  name  propionic  and  the  formula  CH3CH.,COOII,  its  amino  acid,  called 
alanine,  has  the  formula  CH3CHNH2COOH.  Now  let  us  place  the  formu- 
las of  these  two  acids  side  by  side  in  the  following  manner: 

H  CH3 

I  I 

NH2-C-COOH  NH2-C-COOH 

I  I 

(amino  group)     H     (acid  group)  (amino  group)     H     (acid  group) 
Aminoacetic  acid  Aminopropionic  acid 

(glycocoll)  (alanine) 


THE    METABOLISM   OF   PROTEIN  599 

It  will  be  observed  that  the  only  difference  between  the  two  acids  is 
dependent  upon  a  change  in  the  group  thai  is  attached  to  the  upper  verti- 
cal valency  bond  of  the  central  carbon  atom,  which  therefore  must  be 
considered  as  the  center  of  the  entire  molecule.  The  various  amino  acids 
produced  from  protein  differ  from  one  another  solely  with  regard  to  the 
chemical  nature  of  the  group  that  is  attached  to  this  vertical  valency 
bond.  Evidently,  then,  the  reactions  tJiat  amino  acids  possess  in  common 
must  depend  on  the  terminal  groups  containing  the  carboxyl  and  amino 
radicles,  whereas  the  characteristic  reaction  of  each  of  the  eighteen  amino 
acids  must  depend  upon  the  differences  in  the  radicles  attached  to  the 
upper  vertical  bond.     This  may  be  represented  thus: 

Any  radicle 

I 
NH2  -  C  -  COOH 

I 

H 
Any  amino  acid 

The  end  groups  endow  the  amino  acids  with  the  power  to  combine  with 
both  acids  and  bases.  With  acids  they  behave  like  substituted  ammonias 
to  form  salts,  which  can  ionize  into  the  amino  acid,  as  the  cation,  and  the 
acid  group,  as  the  anion.  With  bases  the  carboxyl  group  reacts  to  form 
salts,  which  yield  amino  acid  as  the  anion.  A  most  important  reaction  con- 
sists in  the  condensation  of  aldehydes  with  the  amino  group.  This  occurs 
particularly  readily  with  formaldehyde,  water  being  eliminated  in  the  re- 
action, and  the  basic  nature  of  the  amino  acid  being  thus  destroyed. 
Upon  this  reaction  depends  the  method  of  Sorensen  for  determining  the 
amount  of  amino  acid  in  a  mixture  (see  page  606).  The  titration  is  per- 
formed by  rendering  the  solution  of  amino  acids  neutral,  then  adding 
formaldehyde  and  titrating  with  standardized  acid,  using  phenolphtha- 
lein  as  the  indicator,  and  thus  finding  to  what  degree  the  acidity  of  the 
mixture  has  become  increased  as  a  result  of  adding  the  formaldehyde. 
Since  this  increase  in  acidity  must  depend  upon  the  number  of  amino 
groups,  it  furnishes  us  with  an  indirect  estimate  of  the  concentration  of 
the  amino  acids.    The  reaction  is  illustrated  by  the  equation: 

radicle  H  radicle 

I  I  I 

NH.,-C-COOH  +  H-C  =  0    =    CH..  =  N-  C-  COOH  +  H,0 

I  I 

H  H 

( amino  acid)  (formaldehyde) 

Another  reaction  of  amino  acid  of  physiologic  interest  is  that  known 
as  the  carbamino  reaction,  consisting  in  a  union  of  the  amino  acid  with 
calcium  and  carbonic  acid.    Finally,  it  is  important  to  note  that  the  amino 


GOO  METABOLISM 

group  is  very  firmly  attached;  it  remains  intact  in  acids  and  alkalies  and 
is  removable  only  by  a  process  of  oxidation.  This  can  be  accomplished  by 
treating  the  amino  acid  with  such  reagents  as  hydrogen  peroxide  or  per- 
manganate, when  the  amino  group  is  displaced  and  a  so-called  ketonic  acid 
formed.     The  reaction  will  be  evident  from  the  accompanying  equation : 

CH3  CH3 

I  I 

O  +  NH,  -  U  -  COOII  +±  0  =  U-COOH+  NH3 

I 
H 

(alanine)  (pyruvic  acid) 

To  illustrate  this  reaction  we  have  chosen  aminopropionic  acid  or  ala- 
nine, because  the  substance  formed  by  its  oxidation  and  known  as  pyruvic 
acid  is  of  very  great  importance  in  intermediary  metabolism.  It  serves 
as  the  common  substance  from  which  proteins,  carbohydrates  or  fats  may 
be  formed,  and  therefore  as  the  intermediary  substance  through  which 
one  of  them  may  pass  on  being  transformed  into  another  (page  666).  The 
use  of  two  arrows  pointing  in  opposite  directions  in  the  above  equation 
indicates  that  the  reaction  may  proceed  readily  in  either  direction. 

The  ammonia  set  free  from  amino  acids  may  be  oxidized  to  free  nitrogen 
by  using  nitrous  acid  according  to  the  general  equation:  NH3-|-HONO= 
2H20+N2.  Upon  this  reaction  depends  another  extremely  important 
quantitative  method  for  measuring  the  number  of  amino  groups  present  in 
protein  (Van  Slake).  To  make  the  estimation,  nitrous  acid  is  allowed 
to  act  on  the  amino  acids,  and  the  volume  of  nitrogen  gas  set  free  by  the 
reaction  is  measured,  the  principle  being  similar  to  that  used  for  the  de- 
termination of  urea  by  the  hypobromite  method. 

The  apparatus  employed  for  decomposing  the  substance  and  collecting  and  measuring 
the  evolved  nitrogen  consists  essentially  of  a  mixing  bulb,  connected  below  through  stop- 
cocks with  two  small  burettes,  one  containing  a  solution  of  sodium  nitrite  and  glacial 
acetic  acid,  and  the  other  a  solution  of  the  substance  to  be  investigated.  The  upper  end 
of  the  mixing  bulb  is  connected  through  a  three-way  cock  with  a  graduated  gas  burette 
and  with  another  bulb  containing  potassium  permanganate  solution.  By  allowing  some 
nitrite  and  acid  solution  to  run  into  it  and  shaking,  the  mixing  bulb  is  first  of  all  filled 
to  a  certain  mark  with  nitrous  oxide  gas.  A  measured  quantity  of  the  amino  solution 
is  then  allowed  to  mix  with  the  nitrite;  the  apparatus  is  shaken  for  five  minutes  at  15 
to  20°  C,  and  the  evolved  nitrogen  and  nitric  oxide  are  driven  over  into  the  permanganate, 
which  absorbs  the  nitric  oxide,  leaving  the  nitrogen,  which  is  then  measured  in  the  burette. 

The  apparatus  has  now  been  so  perfected  that  numerous  analyses  may 
be  made  with  it  in  a  very  short  time  and  with  a  degree  of  accuracy  that 
is  scarcely  surpassed  in  any  other  biochemical  estimation. 

From  the  point  of  view  of  protein  chemistry,  the  most  significant  reac- 
tion of  the  amino  acids  is  their  ability  to  link  together  to  form  compounds 


Till      MKTAHOUSM    OF    PROTEIN  G01 

called  peptides.    This  linking  occurs  between  the  amino  group  of  one 

amino  acid  and  the  carboxy]  group  <»i*  the  other.  When  alanine  and  glyco- 
coll, with  which  we  arc  Eamiliar,  arc  thus  linked  together,  the  reaction 
takes  place  according  to  the  equation: 

][  ("11,  H 

cir3         |  !  I 

/ : II  +  HOI    OC  -  C  -  NIL,  —  IIOOC  -  C  -  Nil  -  CO  -  C  -  NIL.  +  H,0 

1IOOC-C-N '  |  I  | 

^        \h  II  II  H 

(alanine)  (glycocoll)  (alanyl  -  glycocoll) 

In  this  manner,  then,  a  so-called  dipeptide  is  formed,  in  which  it  will 
be  observed  there  still  remain  free  carboxyl  and  amino  groups,  thus  per- 
mitting the  linking  on  of  other  amino-aeid  groups  to  form  tripeptides  or 
tetrapeptides  or  other  polypeptides.  Indeed,  this  process  of  condensa- 
tion may  go  on  practically  indefinitely,  a  polypeptide  containing  eighteen 
amino-acid  groups — namely,  three  leucine  and  fifteen  glycocoll  groups — hav- 
ing actually  been  synthesized.  The  resulting  polypeptides  have  the  proper- 
ties of  derived  proteins  like  the  proteoses;  thus,  they  give  the  biuret 
and  other  reactions  characteristic  of  proteins  and  are  precipitated  by 
such  reagents  as  mercuric  chloride  and  phosphotungstic  acid.  Some  are 
also  digested  by  trypsin  and  erepsin.  They  have  the  same  optical  activities 
as  proteins.  One  of  them  has  been  prepared  which  produces  a  typical 
anaphylactic  reaction.  So  far  a  polypeptide  that  can  be  coagulated  by 
heat  or  is  in  other  ways  identical  with  the  naturally  occurring  proteins, 
has  not  been  synthesized ;  but  there  is  no  doubt  that  it  is  only  a  matter 
of  time  before  this  will  be  accomplished. 

Eighteen  distinctly  different  amino  acids  have  been  isolated  from  pro- 
tein, and  it  may  assist  in  the  conception  of  our  problem  if  we  place  these 
amino  acids  side  by  side  and  link  them  together  in  the  manner  described 
above.  This  is  done  in  the  accompanying  chart  compiled  by  D.  D.  Van 
Slyke,  in  Which  also  various  other  important  facts  concerning  the  chem- 
istry of  the  amino  acids  are  incidentally  added. 

At  the  lower  part  of  each  formula  will  be  seen  the  characteristic  car- 
boxvl and  amino  groups  of  neighboring  acids  linking  together  the  ter- 
minal carbon  atoms.  The  upper  vertical  bond  of  this  carbon  atom  is  con- 
nected with  the  characteristic  group  of  the  amino  acid,  which  may  be  very 
simple  and  represented  only  by  hydrogen,  as  in  glycocoll,  or  highly  com- 
plex and  including  a  ring  formation,  as  in  tryptophane.  It  will  further 
be  observed  that  there  may  oe  other  amino  groups  connected  in  various 
positions  in  this  radicle.  This  is  particularly  the  case  in  the  first  three  of 
the  amino  acids  in  the  table — namely,  the  basic  amino  acids.  In  lysine 
the  extra  amino  group  reacts  with  nitrous  acid,  liberating  free  nitrogen 


602 


METABOLISM 


=  1 
i  8  &= 

I    =  J  -i- 

1  -     fc-  f     fi 

3 

| 

O 
<   = 

:  = 

1c 
|S 

It 

*    r- 

^  z 

:| 

i 

6 

0      C 

Z         1 

7     "i1 

P       ° 

C    z        v 

_.    z         | 

C — O — S  5      +       i 
i          < 

\ 
— "                   Z            c 

a    ="      _    z         2 

K                      z         2 

i 

r<tH'-  - 

.  . * — 2           e 

J 

sac 

i 

■< 

^'t — °V      _      z           e 

i-<I>-M-=l  ,  ♦ 

=   =              8 

*T 

1 

=               « 

U                      -           o 

''aria 

i  lu* 

sip  If 

*>  1  - 1 

■  1° 

i     I 

-     ji       .     j.            .     2            e 

2                                                   "                  f        | 

THE    METABOLISM    OP   PROTEIN  603 

by  the  Van  Slyke  method;  but  in  other  cases,  as  in  arginine,  it  fails  to 
give  this  and  the  other  characteristic  reactions  of  the  amino  group.  That 
the  extra  amino  group  in  lysine  reacts  directly  with  nitrous  acid  explains 
why  various  proteins  when  examined  for  amino  nitrogen  yield  an  amount 
that  is  ecpial  to  half  of  the  lysine  nitrogen. 

It  will  further  be  observed  that  the  amino  acids  are  arranged  in  three 
main  groups:  one  basic,  another  neutral,  and  the  third  acid.  The  acids 
of  tlu  basic  group  are  three  in  number  and  have  an  alkalinity  similar  to 
that  of  ammonia.  They  have  been  called  the  hexone  bases,  because  each 
contains  six  carbon  atoms.  They  are  alone  present  in  certain  forms  of  pro- 
tein called  protamines.  The  neutral  amino  acids  contain  one  amino  group 
and  one  carboxyl  group,  which  exactly  neutralize  each  other.  This  is 
the  largest  group  of  amino  acids,  and  is  further  subdivided  into  three : 
one  containing  aromatic  or  benzene  rings  and  including  the  very  im- 
portant amino  acids,  tyrosine  and  tryptophane;  another  containing  the 
so-called  pyrrolidine  ring;  and  the  third,  the  largest  of  all,  containing 
the  so-called  aliphatic  chains ;  that  is,  the  chains  characteristic  of  the 
fatty  acids  and  which  may  be  either  straight  or  branched.  When  the  chains 
are  branched,  the  substance  is  called  an  isosubstance,  as  in  isoleucine. 
The  acid  amino  acids,  including  glutamic  acid  and  aspartic  acid,  are 
characterized  by  containing  two  carboxyl  groups  and  only  one  amino 
group.    They  therefore  resemble  acetic  acid  in  acidity. 

It  may  be  of  assistance  to  some  if  Ave  restate  these  chemical  facts 
from  a  slightly  different  standpoint  as  follows: 

Glycine,  or  glycocoll,  is  aminoacetic  acid,  CH2NH,COOH. 

NH2 

/ 
Alanine   is    glycine   plus    a    methyl   group,    CH3CH  ;   it   is  therefore   amino- 

\ 

COOH 

OH 
/ 
propionic  acid  and  is  closely  related  to  lactic  acid,  which  is  CH,CH  .     Many  of 

\ 

COOH 

the  other  amino  acids  may  be  considered  as  derivatives  of  alanine,  thus: 

1.  Serine  is  alanine  with  an  "OH"   (hydroxyl)   group  in  place  of  one  of  the  "H" 

NH, 

/ 

atoms  of  the  methyl  group,  CH..OH  -  CH 

\ 

COOH 

2.  Cysteine  is  alanine  with  an  "SH"   (thio)  group  in  this  position, 

NH, 

/ 
CH2SH  -  CH 

\ 
COOH 


604 


METABOLISM 


Two  cysteine  molecules  united  at  the  "S"  groups  give  cystine. 

Nil 


/ 


CB  s-CII 


\ 


coon 


NIL 


3.  Phenylalanine  has   a  CCH.    (phenyl)    group,   '  1 1  ' '  IT.  -  CII 


/ 


\ 


4.  Tyrosine  has  a  C,;Ii4OH    (phenol)     group..  CH2C6H4OH  -  CH 


COOH 

NIL, 
/ 


\ 


COOH 


C 

/       \ 
5.  Tryptophane  has  a  C,H<  CH  (indole)  group: 

\        / 
NH 

C  —  CH,  -  CH  -  XH,  -  COOH. 

/       \ 
C6H,  CH 

\        / 
NH 


N 


CH 


NH 

I 


6.  Ilistidine  has  a  CH    =    C  -  (imidazole)  group: 
CH 

N  NH 

I  I 

CH    =    ('.fir     .   CH.    NH,-COOH. 

The  last  two  are  also  called  heterocyclic  compounds,  of  which  there 
is  another,  viz.; 

Proline  (and  oxyproline),  which  is  a-pyrrolidine  carboxylic  acid: 

CH,      —      CH, 

I  I 

CH,  CH.COOH 

\        / 
NH 


Otlur  amino  acids  are: 


(1)  Valine 
Leucine 

Isoleiifinc 

thus: 


CH  CH  CH  CH3        CH3  C:H5 

N    /  \    /  \     / 

CH 


CH.NH, 
COOH 
(valine) 


CH 

I 
CH, 

I 
CH.XIL 

I 
COOH 

(leucine) 


CH 

I 
CH.XH2 

I 
COOH 

(isoleucine) 


THE    METABOLISM    OF    PROTEIN  G05 

(2)  The  amino  dibasic  acjds: 

As|i;ui ic,  which  is  aminosuccinic  acid, 

CH2COOH 

I  " 
CHXIt.COOII  ;  and 
Glutaminie,  which  is  aminoglutaric  arid, 
CH2 

I 

ch,  -  coon 
chnil  coon. 

Lastly  there  arc  the  diamrno  acids,  i"  which  two  groups  oxisl  : 

Lysine  a  e-diaminoeaproic  acid, 

NIL 

/ 

NH.CIL  -  CIL  -  CH,  -  CH.,  -  CH.  -  CH 

\ 

coon. 

Arginine  a-amino — 5-guanidine-valcrianic  acid, 

N  i  r, 
/ 

HN  =  C  NII2 

\  / 

NII.CH,  -  CH2  -  CH,  -  CH 

\ 

COOH 

The  guanidine  group  in  this  acid  is  of  interest  because  of  its  close  relationship  to 

NH2 

/ 
urea,  which  is  O  =  C 

\ 
NIL 


CHAPTER  LXVIII 

THE  METABOLISM  OF  PROTEIN   (Cont'd) 

AMINO  ACIDS  IN  THE  BLOOD  AND  TISSUES 

In  the  Blood. — Furnished  with  the  general  facts  concerning  the  chem- 
istry of  proteins,  we  may  now  proceed  to  consider  the  more  precise 
knowledge  recently  acquired  concerning  the  history  of  this  substance 
in  the  animal  economy.  Although  no  one  has  succeeded  in  separating 
amino  acids  in  pure  condition  from  drawn  blood  even  during  the  height 
of  digestion,  it  has  nevertheless  been  possible  to  do  so  from  circulating 
blood  by  a  method  of  dialysis,  known  as  vividiffuswn,  elaborated  by 
Abel33  and  his  pupils.  The  method  consists  in  connecting  a  long  tube 
of  collodion  with  the  two  ends  of  a  cut  artery  in  an  anesthetized  animal. 
The  tube,  coiled  many  times,  is  then  immersed  in  a  solution  containing 
approximately  the  same  salt  content  as  the  blood  plasma  of  the  animal. 
The  diffusible  constituents  of  the  blood  plasma  dialyze  into  the  saline 
solution ;  or  any  one  of  them  may  be  prevented  from  dialyzing  by  adding 
that  particular  substance  to  the  saline  in  such  amounts  as  will  make  its 
concentration  in  plasma  and  saline  alike.  In  some  ways,  it  will  be  seen, 
the  apparatus  may  be  considered  as  an  artificial  kidney.  Its  possible 
clinical  application  for  the  purpose  of  removing  poisons  from  the  blood 
is  under  investigation.  It  has  been  possible  in  this  way  to  isolate  several 
of  the  amino  acids  and  other  ammonia-yielding  substances  from  blood. 
Thus,  alanine  and  valine  have  been  obtained  as  crystalline  salts,  and 
histidine  and  creatine  (see  page  622)  shown  to  be  present  by  their  reac- 
tions. All  of  the  amino  substances,  however,  do  not  dialyze,  and  these 
exceptions  are  further  characterized  by  the  fact  that  they  do  not  readily 
give  up  their  ammonia  on  the  addition  of  sodium  carbonate,  as  do  the 
diffusible  substances  (Rohde).  Although  amino  acids  can  thus  be  sepa- 
rated in  a  pure  state  from  circulating  blood,  their  concentration  in  -a 
drawn  specimen  is  too  low  to  make  direct  quantitative  estimation  possible. 
By  the  methods  of  Van  Slyke  and  Sorensen,  already  described,  however, 
it  has  been  shown  among  other  things  that  the  blood  always  contains  a 
certain  concentration  of  amino  acids ;  thus,  in  that  of  fasting  animals  from 
3  to  5  mg.  per  100  c.c.  of  blood  are  usually  found  present.  During  the 
absorption  of  a  protein  meal,  the  amino  content  of  the  blood  undergoes 

606 


Till:     MKTAI'.OI.ISM     OF    IMtOTKIX 


607 


a  marked  increase,  becoming  doubled  or  more;  and  a  similar  result  lias 
been  obtained  by  placing  pure  amino  acids  in  the  small  intestine.  After 
10  grams  of  alanine,  tor  example,  the  amino  nitrogen  of  the  mesenteric 
blood  tiisc  from  3.7  to  6.15  mg.  per  cent.* 

In  the  Tissues. — After  entering  the  circulation,  the  amino  acid  very 
quickly  disappear  from  it  again.  This  has  been  demonstrated  by  ob- 
serving the  amount  of  amino  aeids  in  the  hlood  after  intravenously 
injecting  a  solution  of  amino  acid  into  an  anesthetized  animal.  After 
injecting  12  gm.  of  alanine  into  the  vein  of  a  dog,  90  per  cent  "was  found 


Fig.    U 


-Yividiffusion  apparatus  of  J.  J.  Abel. 


to  have  disappeared  from  the  circulation  within  five  minutes.  The  ques- 
tion is,  "What  becomes  of  the  amino  acids  that  rapidly  disappear?  Are 
they  decomposed  in  the  blood,  or  do  they  become  absorbed  by  the  tis- 
sues? This  problem  has  been  attacked  by  analyzing  portions  of  various 
organs  and  tissues  removed  before  and  some  time  after  the  injection 
into  an  animal  of  amino  acid  solutions.  In  the  case  of  the  muscles  it 
has  been  found  that  the  amino-acid  content  increases  until  from  60  to 
80  mg.  per  cent  of  amino  acid  has  accumulated.  Beyond  this  point, 
however,  the  muscles  do  not  seem  to  be  able  to  take  up  any  more  amino 
acid.     The  capacity  of  the  intestinal  organs,  however,  is  more  elastic; 

"This  is  a  convenient  way  of  stating  per   100  c.c.  of  blood. 


608 


METABOLISM 


for  example,  the  amino  nitrogen  of  the  liver  has  been  observed  to  become 
increased  to  125  or  150  mg.  per  cent  of  the  original  amount.  Although 
this  absorption  of  amino  acids  by  the  tissues  is  extremely  rapid,  it  never 
proceeds  to  such  a  point  that  the  blood  becomes  entirely  free  of  them. 
Even  after  many  days'  starvation  the  blood  contains  its  normal  quota 
of  from  3  to  10  mg.  per  100  gm.  of  moist  tissue  (Fig.  188).  This  indicates 
that  a  certain  equilibrium  must  become  established  between  the  amino-acid 
content  of  the  blood  and  that  of  the  tissues,  the  concentration  in  the  tissues 
being  approximately  from  five  to  ten  times  greater  than  in  the  blood. 


150 


100 


1  3 

Hours 
Fig.    187. — Curves    showing   the    amount    of    amino    nitrogen    taken    up    by    different    tissues    after 
the   cutaneous  injection   of  amino   acids.      The   lowermost  curve  shows  the   urea   concentration   of  the 
blood.      (From  D.  D.   Van  Slyke.) 

The  absorbed  amino  acids  are  very  loosely  combined  with  the  tissues, 
for  they  can  be  extracted  by  such  feeble  reagents  as  water  or  dilute  al- 
cohol. Their  presence  can  not,  however,  be  merely  due  to  diffusion; 
for  if  it  were,  the  concentration  could  not  become  greater  in  the  tis- 
sues than  in  the  blood.  The  further  fate  of  the  amino  acids  is  difficult 
to  follow.  We  know  that  they  do  not  remain  in  the  body  for  a  long  time, 
because  most  of  the  protein  nitrogen  in  the  food  is  excreted  as  urea 
within  twenty-four  hours  after  ingestion ;  and  when  single  amino  acids 
are  fed,  they  quickly  reappear  in  the  urine  as  urea. 


THi:     MKTAI'.OI.ISM     OF    I'KOTF.IN 


609 


The  tissues  can  therefore  be  only  a  stopping-place  for  the  amino 
acids.  When  the  latter  are  determined  in  blood  collected  from  different 
parts  while  absorption  of  protein  from  the  intestine  is  in  process,  it 
has  been  found,  as  shown  in  Fig.  188,  that  during  the  passage  of  the 
blood  through  the  liver  there  is  a  greater  fall  in  the  concentration  of 
amino  acids  than  during  its  passage  through  the  entire  remainder  of 
the  body. 

It  will  be  seen  that  the  above  conclusions  are  drawn  from  estima- 
tions made  on  blood  taken  from  the  vena  cava,  portal  vein,  and  hepatic 


Fig.    188. — Curves   showing   the    concentration   of    amino-acid    nitrogen    in    the   blood    during    fasting 
and  protein  digestion.     (From  D.  D.  Van  Slyke.) 


artery,  the  upper  curves  in  the  chart  being  from  animals  during  digestion 
and  the  lower  from  fasting  animals.  The  results  show  that  the  liver  must 
be  particularly  greedy  of  amino  acids,  wrhich,  however,  must  rapidly  be- 
come transformed  into  other  substances,  since  no  conspicuous  varia- 
tion has  been  found  to  occur  in  the  amino-acid  content  of  the  tissues 
according  to  whether  the  animal  is  fasting  or  is  digesting  protein  food. 
This  result,  it  is  to  be  noted,  is  quite  different  from  that  which  is  ob- 
tained after  the  intravenous  injection  of  amino  acids,  and  the  results  of 


610  METABOLISM 

the  two  experiments  taken  together,  indicate  that  the  amino  acids  after 
their  absorption  can  not  remain  in  the  tissues  in  a  free  condition  for  a 
long  time.  It  means  that  tlic  amino  acids  during  natural  digestion  must 
be  disposed  of  at  a  rate  which  is  practically  the  same  as  that  at  which  ab- 
sorption is  proceeding. 

THE  FATE  OF  THE  AMINO  ACIDS 

To  follow  the  metabolism  of  the  amino  acids  further  we  must  deter- 
mine the  end  product  into  which  they  are  converted.  This  is  urea, 
whose  estimation  can  nowadays  be  made  with  considerable  accuracy  on 
account  of  the  discovery,  by  Marshall,  of  the  action  of  urease  in  con- 
verting its  nitrogen  into  ammonia,  which  can  then  be  estimated  by  com- 
paratively simple  methods  (Folin). 

"When  the  viscera  are  compared  before  and  at  various  periods  after 
the  intravenous  injection  of  amino  acids,  the  immediate  increase  in 
amino  nitrogen  remains  undiminished  in  all  of  them  except  the  liver,  in 
which  a  very  rapid  reduction  is  observed  to  occur.  At  the  same  time 
the  percentage  of  urea  in  the  blood  steadily  rises.  These  facts  are  illus- 
trated in  Fig.  187. 

The  simplest  interpretation  of  these  results  is  that  the  liver  converts 
the  amino  acids  into  urea  and  discharges  this  urea  into  the  blood.  This 
conclusion,  however,  it  must  be  observed,  is  not  inevitable;  for  it  is  pos- 
sible that  the  amino  acids  may  be  condensed  into  polypeptides  in  the 
liver,  just  as  sugar  is  condensed  by  this  organ  into  glycogen,  and  that 
the  increase  in  urea  is  merely  coincident   (Fiske). 

It  must  not  be  imagined  that  the  conversion  of  the  amino  acids  into 
urea  is  exclusively  a  function  of  the  liver.  On  the  contrary,  it  is  well 
known  that  this  process  may  occur  in  animals  from  which  the  liver  ha? 
been  entirely  removed.  It  is  probably  safe  to  conclude,  however,  that 
the  liver  is  the  most  active  center  for  amino-acid  transformation  and 
urea  formation. 

When  urea  is  estimated  in  samples  of  blood  removed  at  short  inter- 
vals of  time  after  the  ingestion  of  a  large  amount  of  protein,  it  is  found 
that  the  increase  becomes  very  early  established.  In  one  experiment, 
before  the  food  was  taken  the  concentration  of  urea  nitrogen  in  the  blood 
was  a  little  over  10  mg.  per  cent;  one  hour  after  taking  500  grams  of 
meat,  it  had  risen  to  about  18,  and  in  two  hours  to  nearly  25.  Evidently 
the  increase  had  occurred  about  the  same  time  as  the  passage  of  food 
from  the  stomach  into  the  duodenum.  These  facts  indicate  that  urea 
formation  in  the  liver  becomes  stimulated  long  before  the  other  tissues, 
such  as  the  muscles,  have  had  time  to  take  up  their  full  quota  of  amino 


tiii:    METABOLISM    OF    PROTEIN  OH 

acids.  During  digestion  of  protein  tlio  liver  docs  not  appear  to  wait 
until  the  other  tissues  have  become  saturated  with  amino  acids  before  it 
begins  to  destroy  (lie  mi neeessa rv  excess  by  conversion  into  urea;  on 
the  contrary,  this  process  sets  in  with  the  very  first  installment  of  amino 
acid  that  reaches  the  liver  by  the  portal  blood.  This  conclusion  is  in 
harmony  -with  the  veil-established  fact  that,  when  protein  is  given  to  a 
starving  animal,  the  greater  part  of  its  nitrogen  is  soon  excreted  as 
area,  leaving  only  a  small  fraction  to  be  used  for  rebuilding  the  wasted 
tissues  ( see  page  643). 

The  amino  acids  that  are  absorbed  by  the  extrahepatic  tissues  become 
very  quickly  converted  into  formed  protein,  as  is  evident  from  the  fact 
that  the  concentration  of  free  amino  acids  in  the  tissues  of  an  animal 
during  absorption  of  protein  is  not  perceptibly  greater  than  in  those  of 
a  fasting  animal,  and  the  question  remains  to  be  considered,  What  he- 
comes  of  the  protein  thus  formed?  The  answer  is,  that  it  is  gradually 
used  up  in  the  metabolic  processes,  so  as  to  liberate  again  the  amino 
acids,  which  add  themselves  to  those  absorbed  from  the  intestine  and  be- 
come used  again  or  excreted,  according  to  the  demands  of  the  tissues  at 
the  time  for  amino  acid. 

This  process  of  liberation  of  amino  acid  from  the  breakdown  of  body 
protein  goes  on  of  course  irrespective  of  absorption  of  amino  acid  from 
the  intestine.  It  goes' on,  for  example,  during  starvation;  indeed,  in 
this  condition  the  percentage  of  free  amino  acids  in  the  muscles  is,  if 
anything,  somewhat  higher  than  that  observed  in  an  ordinarily  fed  an- 
imal. In  starvation  also  the  migration  of  amino  acid  is  going  on  among 
the  various  organs,  of  which  those  whose  activity  is  essential  to  the 
maintenance  of  life,  such  as  the  heart  and  the  respiratory  muscles,  are 
supplied  with  amino  acids  from  tissues  that  are  less  vital,  such  as  the 
skeletal  muscles  (see  page  568).  These  experiments  further  show  that 
free  amino  acids  can  not  serve  to  any  significant  extent  as  food  reserves 
in  the  same  way  as  glycogen  and  fat.  If  amino  acids  were  of  value  as 
food  reserves,  we  should  expect  the  store  of  them  to  be  depleted 
by  starvation.  As  to  how  long  a  period  of  time  elapses  between  the 
incorporation  of  the  absorbed  amino  acids  into  tissue  protein  and  their 
subsequent  liberation  again  by  autolysis,  we  are  entirely  ignorant. 

The  researches  which  Ave  have  just  been  considering  do  not  throw  any 
light  on  the  relative  value  of  different  proteins  in  tissue  metabolism. 
They  do  not  inform  us  as  to  which  of  the  amino  acids  must  be  absorbed 
ready-made  from  the  digested  food,  and  which  of  them  may  be  dispensed 
with  since  the  organism  can  manufacture  them  for  itself.  We  know  that 
the  higher  animals  can  synthesize  some  amino  acids,  such  as  glycocoll, 
but  not  others,  such  as  tryptophane;  but  which  amino  acids  belong  to 


612  METABOLISM 

the  glycocoll  and  which  to  the  tryptophane  groups,  can  not  as  yet 
be  definitely  stated.  The  investigation  of  this  problem  has  to  be  under- 
taken by  experiments  of  an  entirely  different  type — namely,  by  observing 
the  welfare  and  growth  of  animals  fed  on  proteins  of  varying  amino- 
acid  composition.  A  full  discussion  of  these  experiments  is  given  in 
the  chapters  on  Nutrition  and  Growth. 


CHAPTER  LXIX 
THE  METABOLISM  OF  PROTEIN  (Cont'd) 

THE  END  PRODUCTS  OF  PROTEIN  METABOLISM 

Introductory. — So  far  Ave  have  approached  the  problem  of  protein 
metabolism  by  studying  the  behavior  of  the  absorbed  products  of  pro- 
tein breakdown,  and  we  have  seen  that  these  become  gradually  assimilated 
by  the  tissues  and  used  by  them  in  their  metabolic  processes.  We  have 
been  unable,  however,  to  offer  any  facts  regarding  the  exact  chemical 
changes  which  each  amino  acid  undergoes  during  this  process  of  tissue 
metabolism.  At  first  sight  it  might  appear  an  easy  matter  to  collect 
such  information  by  direct  examination  of  the  tissues  themselves,  either 
by  searching  in  them  for  amino  derivatives  which  might  be  derived  from 
absorbed  amino  acids,  or  by  studying  the  changes  which  occur  when 
the  amino  acids  are  subjected  to  the  action  of  the  isolated  tissue  en- 
zymes that  must  be  responsible  for  the  change.  Such  methods  of  in- 
vestigation are,  however,  fraught  with  technical  difficulties  so  great  that 
very  little  can  be  learned  from  them,  and  for  the  present  at  least  we 
must  be  content  to  piece  our  information  together  from  facts  derived 
by  less  direct  methods.  Such  a  method  is  offered  by  investigating 
the  behavior  of  the  end  products  of  protein  metabolism. 

The  main  end  product  is  urea  along  with  traces  of  its  precursor  am- 
monia, but  these  are  not  the  only  ones,  for  some  amino  acids  after  being 
incorporated  with  the  tissue  proteins  break  down  into  products  that 
are  no  longer  members  of  the  amino-acid  series,  although  they  may  be 
closely  related  to  certain  amino  ocids.  Such  substances  are  creatine  and 
its  anhydrid  creatinine.  A  part  of  the  amino  acids  during  their  pres- 
ence in  a  free  state  in  the  blood  may  also  be  excreted  unchanged  by 
the  kidney.  Our  list  so  far  therefore  includes  urea,  ammonia,  creatine, 
creatinine,  and  amino  nitrogen,  of  which  the  last  is  usually  included  in 
metabolism  investigations  in  the  fraction  designated  undetermined 
nitrogen. 

Another  group  of  closely  related  substances  coming,  not  from  the 
general  protein  metabolism  of  the  tissues,  but  from  the  metabolism 
which  is  peculiar  to  the  nuclei,  consists  of  the  so-called  purine  oodies. 
Furthermore,  so  as  to  serve  as  a  check  on  results  obtained  by  examining 
these  nitrogenous  metabolites,  it  is  important  to  observe  the  manner  of 

613 


614 


METABOLISM 


excretion  of  the  sulphur  moiety  of  the  protein  molecule,  for  it  Avill  he 
remembered  that  it  is  in  protein  alone  that  sulphur  is  usually  taken  into 
the  animal  body.  The  excretion  of  sulphur  therefore  runs  more  or  less 
parallel  with  the  intensity  of  protein  metabolism. 

After  selecting  the  end  products  that  are  most  likely  to  be  of  signif- 
icance, the  first  question  concerns  the  amount  of  each  of  them  excreted 
during  twenty-four  hours  on  diets  that  are  either  rich  or  poor  in  pro- 
tein. The  possibility  of  conducting  such  investigations  obviously  de- 
pends on  the  use  of  quick  and  yet  reliable  methods  for  the  estimation 
of  the  nitrogenous  metabolites.  Such  methods  have  been  furnished  by 
the  painstaking  and  careful  work  of  Folin,  an  example  of  whose  results 
are  given  in  the  accompanying  table. 


NITFvOGEN-KICH   DIET 

NITROGEN-POOR    DIET 

Volume  of  urine 

1170    C.C. 

385  c.c. 

Total  nitrogen 

16.8  grams 

3.60  grams 

Urea  nitrogen 

14.7     grams  =  87.5% 

2.20  grams 

=  61.7% 

Ammonia  nitrogen 

0.49  gram    =    3.0% 

0.42  gram 

=  11.3% 

Uric-acid  nitrogen 

0.1S  gram    —    1.1% 

0.09  gram 

=    2.5% 

Creatinine  nitrogen 

0.58  gram    =    3.6% 

0.60  gram 

=  17.2% 

Undetermined  nitrogen 

0.S5  gram    —    4.9% 

0.27  gram 

=    7.3% 

Total  S03 

3.64  grams 

0.76  gram 

Inorganic  S03 

3.27  grams  =  90.0% 

0.46  gram 

=  60.5% 

Ethereal  S03 

0.19  gram    =    5.2% 

0.10  gram 

=  13.27„ 

Neutral  SO, 

0.18  gram    =    4.8% 

0.20  gram 

=  26.3% 

(Folin.) 

The  general  conclusions  which  may  be  drawn  from  these  results  are 
as  follows: 

1.  With  a  protein-rich  diet  much  more  urine  is  excreted  in  twenty- 
four  hours  than  with  one  that  is  protein-poor.  Evidently  the  nitrogenous 
metabolites  act  as  diuretics. 

2.  The  total  or  absolute  amounts  of  nitrogen  and  of  all  the  other 
nitrogenous  metabolites,  save  creatinine,  become  diminished  during  the 
starvation  period.  The  same  is  true  of  the  sulphur  derivatives,  except 
in  the  case  of  the  neutral  sulphur,  which  behaves  like  creatinine. 

3.  The  decrease  in  the  portion  of  nitrogen  excreted  as  urea  is  relatively 
greater  than  the  decrease  in  total  nitrogen,  this  fact  being  shown  in  the 
table  by  the  percentage  figures,  which  were  secured  by  calculating 
the  proportion  of  nitrogen  in  the  various  substances  as  a  percentage 
of  the  total  nitrogen  excreted  during  the  periods.  The  inorganic  sul- 
phate behaves  in  a  manner  similar  to  the  urea — that  is,  the  percentage 
of  total  sulphate  excreted  in  the  inorganic  form  becomes  much  less 
during  starvation. 

4.  The  relative  amount  of  all  the  other  nitrogenous  metabolites,  as 
well  as  that  of  the  ethereal  and  neutral  sulphates,  becomes  increased 
during  starvation. 


THE    METABOLISM    OF    PROTEIN  615 

The  most  striking  results  of  the  above  investigation  are  thai  creatinine 
remains  unchanged  during  starvation,  but  thai  area  becomes  relatively 
increased.  The  former  tnusl  be  derived  from  metabolic  processes  going 
on  in  the  tissues  independently  of  the  supply  of  foodstuff  carried  to 
them,  whereas  the  latter  must  depend,  if  no1  entirely,  ye1  very  largely, 
on  the  protein  contenl  of  the  food.  Creatinine  may  therefore  be  called 
an  end  produd  of  endogenous  metabolism,  and  urea  an  end  product  of 
exogenous  metabolism. 

Other  metabolites — namely,  ammonia,  uric  acid  and  the  undetermined 
nitrogen,  as  well  as  the  ethereal  sulphates — must  represent  processes 
of  metabolism  thai   are  partly  exogenous  and  partly  endogenous. 

Having  made  ourselves  acquainted  with  the  general  nature  of  the 
changes  that  occur  in  the  nitrogenous  metabolites  when  protein  metab- 
olism is  stimulated  by  the  taking  of  food  or  depressed  by  starvation, 
Ave  may  now  proceed  to  take  up  each  of  the  metabolites  separately  and 
see  what  other  information  can  be  obtained  regarding  their  source  and 
origin  in  the  animal  body. 

UREA  AND  AMMONIA 

For  various  reasons  it  is  important  to  consider  these  two  metabolites 
together.  During  the  intermediary  metabolism  of  the  majority  of  the 
amino  acids,  the  amino  group  becomes  broken  off  as  ammonia,  which 
immediately  combines  with  the  available  acids  to  form  neutral  ammonium 
salts.  The  most  available  acid  for  this  purpose  is  carbonic  acid;  there- 
fore ammonium  carbonate  is  formed  in  large  amounts.  A  small  propor- 
tion of  the  ammonia  may  combine  with  other  acid  radicles,  such  as 
chlorine,  to  form  ammonium  chloride.  The  fate  of  these  two  types  of 
salt  is  very  different.  The  ammonium  carbonate  becomes  quickly  trans- 
formed into  urea,  whereas  the  ammonium  chloride  is  excreted  in  the 
urine.  The  process  of  urea  formation  may  therefore  be  considered  as" 
having  the  function  of  preventing  the  accumulation  of  ammonium  car- 
bonate in  the  animal  body.  It  is  the  means  by  which  a  harmful  substance 
is  converted  into  an  innocuous  substance — a  detoxication  process,  in 
other  words. 

Regarding  the  nature  of  tlic  chemical  process  involved  in  this  trans- 
formation of  ammonium  carbonate  into  urea,  reference  to  the  formulas 
below  will  show  that  the  ammonium  carbonate  that  is  formed  by  the 
union  of  carbonic  acid  with  ammonia,  by  losing  one  molecule  of  water 
becomes  ammonium  carbamate,  which  by  repetition  of  the  process  be- 
comes transformed  into  urea : 


616 


METABOLISM 

OH                                 ONH4                              ONH4 

/                                    /                                     / 
CO             +2NH3;p>CO                  -  H20  <r±  CO                -H20: 

\                                  \                                   \ 

OH                                ONH4                             NH2 

NHS 

/ 
=  CO 

\ 
NH. 

(carbonic       (ammo-        (ammonium                 (ammonium 
acid)             nia)             carbonate)                  carbamate) 

(urea) 

Some  of  the  urea  may  come  from  metabolic  processes  of  an  entirely 
different  type.  One  of  these  at  least  is  known ;  namely,  the  splitting-oil 
of  urea  from  arginine,  which  it  will  be  remembered  is  guanidine-amino- 
valerianic  acid  (see  page  605).  An  enzyme  called  arginase,  having  this 
action,  has  been  isolated  from  various  organs  and  tissues.  The  diamino- 
valerianic  acid,  or  ornithine,  which  remains  after  the  urea  is  split  off, 
may  be  further  used  in  protein  metabolism.  The  reaction  is  shown  in 
the  following  equation: 

NH,  -  C  -  NH  -  CH2  -  CH2  -  CH2  -  CHNH2  ^  COOH  +  H.,0 

II 

NH  (arginine) 

—  NH,  -  CO 

|         +NH,-CH2-CH2-CH2-CHNH2-COOH 
NH2 

(urea)  (ornithine) 

On  an  ordinary  diet,  as  we  have  seen,  a  man  excretes  somewhat  more 
than  90  per  cent  of  his  total  nitrogen  as  urea  and  about  3  per  cent  as 
ammonia,  the  remainder  of  the  nitrogen  appearing  in  the  other  nitrog- 
enous metabolites. 

Influence  of  Acidosis  on  Ammonia-Urea  Ratio. — It  sometimes  happens 
that  a  large  proportion  of  the  ammonia  is  not  converted  into  urea,  but 
is  used  for  the  purpose  of  neutralizing  abnormal  acids  present  in  the 
organism.  When  mineral  acids  are  given  to  an  animal,  or  when  acids 
are  produced  in  the  organism  itself  by  some  faulty  type  of  metabolism, 
the  ammonia  excretion  by  the  urine  immediately  rises.  In  diabetes,  for 
example,  where  considerable  quantities  of  /3-oxybutyric  acid  are  pro- 
duced (see  page  683),  a  decided  increase  in  the  ammonia  excretion  by 
the  urine  is  observed.  A  milder  type  of  acidosis  may  also  be  induced 
in  normal  persons  by  withholding  carbohydrates  from  the  diet,  and 
here  again  the  ammonia  excretion  is  relatively  increased. 

In  such  cases  it  is  quite  evident  that  ammonia  is  used  as  an  alkaline 
reserve  of  the  body ;  that  is,  as  a  substance  which  is  capable  of  prevent- 
ing acidosis  by  neutralizing  the  acids.  It  does  not  appear,  however, 
that  all  types  of  acidosis  entail  the  utilization  of  ammonia  as  reserve 
alkali,  and  an  increase  in  the  relative  amount  of  ammonia  in  the  urine 
does  not  necessarily  indicate  a  condition  of  acidosis.     In  the  pernicious 


THE    METABOLISM    OP   PROTEIN  617 

vomiting  of  pregnancy,  for  example,  a  relatively  high  excretion  of  am- 
monia has  been  found  associated  with  no  greater  a  degree  of  acidosis,  as 
determined  by  the  power  of  the  plasma  to  absorb  carbonic  acid,  than  in 
normal  cases  of  pregnancy. 

Influence  of  Liver  on  Ammonia-Urea  Ratio. — Experimental  Observa- 
tions: (1)  Removal  of  Liver. — There  are  several  facts  which  indicate  that 
other  causes  than  acid-production  may  interfere  with  the  conversion  of  am- 
monia into  urea.  What  are  these  causes?  Since,  as  we  have  seen, 
the  liver  is  the  organ  which  most  actively  converts  amino  acids 
into  urea,  it  would  be  natural  to  expect  that,  when  the  functions  of 
this  organ  were  interfered  with,  relatively  more  of  the  nitrogen  excre- 
tion would  occur  as  ammonia  and  relatively  less  as  urea.  In  order  to 
determine  the  exact  significance  of  the  liver  as  a  urea-forming  organ, 
two  types  of  investigation  have  been  used;  namely,  (1)  observation  of 
the  changes  produced  in  the  ammonia-urea  ratio  in  the  urine  by  partial 
or  total  removal  of  the  liver;  and  (2)  observation  of  the  urea-forming 
power  of  a  liver  perfused  outside  the  body. 

To  remove  the  liver  from  the  circulation  the  portal  vein  is  brought 
in  apposition  with  the  vena  cava,  the  two  are  sewed  together,  and  a 
passage  opened  between  them,  after  which  the  portal  vein  is  ligated  above 
the  anastomosis  (forming  the  so-called  Eck  fistula).  The  portal  blood 
then  passes  directly  into  the  vena  cava,  and  the  liver  is  now  supplied 
only  by  the  hepatic  artery.  The  animals  live  for  a  considerable  time 
after  the  operation,  and  the  urine  frequently  contains  relatively  less 
urea  and  more  ammonia  than  normal.  The  results  are,  however,  not 
nearly  so  striking  as  would  be  expected  if  the  liver  were  the  main  seat 
of  urea  formation.  The  experiments  have  nevertheless  brought  to  light 
a  fact  of  considerable  clinical  interest — namely,  although  the  animals 
may  thrive  if  kept  on  a  diet  not  containing  an  excess  of  flesh,  they  im- 
mediately begin  to  develop  peculiar  symptoms,  not  unlike  those  of  ec- 
lampsia or  uremia,"  when  they  are  fed  with  large  amounts  of  flesh  food. 
Most  of  the  symptoms  can  be  referred  to  abnormal  stimulation  of  the 
central  nervous  system,  and  examination  of  the  urine  has  shown  a  large 
increase  in  the  excretion  of  ammonia  and  a  change  from  the  normal 
acid  reaction  to  an  alkaline  one. 

At  one  time  it  was  assumed  that  the  toxic  symptoms  were  caused  by 
the  presence  in  the  blood  of  ammonium  carbamate,  since  large  quantities 
of  the  calcium  salt  of  this  substance  could  be  separated  from  the  urine. 
It  is  now  known,  however,  that  the  ammonium  carbamate  is  present  only 
because  of  the  excess  of  ammonium  carbonate,  the  two  salts  existing  to- 
gether in  solution  according  to  the  laws  of  mass  action.  That  the  intox- 
ication is  not  due  to  ammonium  carbamate  does  not  exclude  the  pos- 


618  METABOLISM 

sibility  that  it  may  be  due  to  ammonia  itself,  although  it  is  more  likely 
that  other  nitrogenous  metabolites,  produced  when  excess  of  flesh  food 
is  taken,  are  the  responsible  agents. 

If  the  liver  is  entirely  removed  by  ligating  the  hepatic  arteries  in  an 
animal  with  an  Eck  fistula,  a  more  pronounced  decrease  in  urea  and 
increase  in  ammonia  occur  during  the  short  period  of  time  that  the 
animal  survives  the  operation. 

The  results  observed  after  the  removal  or  diminution  of  liver  function 
fail  to  occur  when  other  viscera  are  removed  from  the  animal,  which 
would  at  least  tend  to  indicate  that  the  liver  is  very  important  in  the 
manufacture  of  urea  out  of  ammonia.  This  does  not,  however,  warrant 
the  conclusion  that  the  liver  is  the  only  place  in  the  animal  body  in  which 
such  a  process  occurs. 

In  corroboration  of  these  observations  on  mammals,  it  may  be  of  in- 
terest to  note  that  when  the  liver  is  removed  from  birds,  which  is  a  com- 
paratively simple  operation  on  account  of  a  natural  anastomosis  between 
the  portal  and  renal  veins,  there  is  a  marked  decrease  in  the  excretion 
of  uric  acid  and  a  corresponding  increase  in  the  excretion  of  ammonia 
during  the  twelve  hours  or  so  that  the  birds  survive.  In  birds  and 
reptiles  urea  is  excreted  as  uric  acid,  being  produced  by  a  synthetic 
process  in  the  liver  (see  page  644.).  The  changes  in  this  experiment  are 
of  considerable  magnitude;  thus,  before  the  operation  the  amount  of 
ammonia  nitrogen  relative  to  total  nitrogen  has  been  found  to  vary  be- 
tween 10  and  18  per  cent;  after  the  operation  it  may  be  increased  to 
between  45  and  60  per  cent.  The  uric-acid  nitrogen  normally  varies  be- 
tween 60  and  70  per  cent  of  the  total  nitrogen ;  after  the  operation  it  may 
fall  to  between  3  and  6  per  cent. 

In  animals  with  an  Eck  fistula  and  with  the  hepatic  artery  ligated, 
an  increase  in  the  urea  output  occurs!  when  amino  acids  are  injected  under 
the  skin.  This  result  corroborates  the  conclusion  that  the  liver  can  not 
alone  be  responsible  for  the  conversion  of  ammonia  into  urea. 

(2)  Perfusion  op  Organs. — -This  method  consists  in  removing  the  or- 
gan into  a  warm  chamber  or  bath  and  perfusing  it,  through  cannulas 
inserted  in  its  main  artery  and  vein,  with  a  solution  of  defibrinated  blood 
or  of  defibrinated  blood  mixed  with  saline  solution.  The  perfusion 
liquid  is  kept  at  body  temperature  and  is  saturated  with  oxygen.  By 
means  of  a  pump  it  is  made  to  circulate  in  a  pulsatile  flow,  and  the  total 
amount  of  urea  or  other  metabolite  in  the  circulating  fluid  is  determined 
before  and  after  the  fluid  has  been  circulated  several  times  through  the 
organ.  When  the  liver  is  perfused,  urea  gradually  accumulates  in  the 
fluid,  particularly  after  the  addition  of  one  of  its  known  precursors — 
for  example,  ammonium  carbonate.     When  other  organs  or  viscera  are 


THE    METABOLISM    OF    PROTEIN  619 

perfused,  no  urea  is  formed.  The  evidence  shows  thai  the  liver  is  an 
important  scat  of  urea  formation,  but  not  necessarily  thai  other  organs 
are  unable  to  form  it  in  the  intact  animal,  for  there  arc  many  sources 
of  inaccuracy  in  perfusion  experiments.     Even  though  we  exercise  the 

greatest  care,  we  can  not  hope  to  maintain  the  organ  in  other  than  a 
slowly  dying  condition.  It  is  certainly  far  removed  from  the  normal 
stale,  as  is  revealed  not  only  by  histologic  examination,  hut  by  the  fact 
that  edema  almost  invariably  sets  in  and  the  blood  vessels  hecome  ex- 
tremely constricted,  thus  necessitating  a  gradual  increase  in  the  per- 
fusion pressure  as  the  perfusion  goes  on.  Furthermore,  the  organ  being 
isolated  from  the  nervous  system,  there  can  be  no  control  of  the  rela- 
tive blood  supply  of  different  parts.  In  the  intact  animal  the  circula- 
tion is  more  or  less  distributed  according  to  the  particular  needs  of  the 
different  viscera,  and  such  conditions  obviously  can  not  be  simulated  in 
a  perfusion  experiment.  Another  objection  depends  on  the  fact  that 
the  well-being  of  the  organs  in  the  intact  animal  is  largely  dependent  on 
hormones  conveyed  to  them  from  other  organs.  Such  hormones  are 
frequently  quite  labile  in  nature,  and  soon  disappear  from  the  perfusion 
fluid. 

Notwithstanding  these  objections,  there  can  he  no  doubt  that  many 
of  the  functions  of  an  organ  are  retained  much  longer  than  they  would 
be  if  the  organ  were  not  perfused;  for  example,  the  contractility  of  the 
muscle  or  the  power  of  forming  urea  in  the  liver.  Perfusion  experiments 
are  of  value  therefore  when  they  yield  positive  results.  Negative  re- 
sults may  indicate  either  that  the  organ  does  not  perform  the  particular 
function  that  is  being  investigated  or  that  it  has  lost  this  function  as  a 
result  of  partial  death.  That  a  perfused  muscle  retains  its  power  of 
contraction  does  not  necessarily  indicate  that  it  maintains  all  of  its 
metabolic  functions ;  neither  does  the  fact  that  the  liver  forms  urea 
prove  that  it  is  capable  of  performing  its  other  functions.  It  is  easy  to 
show  that  the  liver  dies  piecemeal;  some  functions,  such  as  glycogen- 
formation,  die  early,  while  others,  such  as  urea-formation,  remain  for  a 
long  time  intact.  The  use  of  perfusion  experiments  for  the  settling  of 
questions  of  metabolism  should  therefore  always  be  very  carefully  con- 
trolled and  never  used  as  the  sole  line  of  evidence  on  which  to  base  impor- 
tant conclusions. 

(3)  Before  leaving  this  subject  it  may  be  well  to  point  out  that  the 
method  which  at  first  sight  might  appear  to  be  the  simplest  for  settling  such 
questions — namely,  the  examination  of  the  inflowing  and  outflowing  blood 
of  different  parts  or  organs — is  not  applicable  in  most  cases.  This  is  be- 
cause of  the  extremely  small  changes  in  concentration  which  may  occur 
even  although  large  amounts  of  the  particular  substance  in  question 


620  METABOLISM 

are  being  absorbed  or  produced.  As  we  shall  see  later,  this  criticism  is 
particularly  applicable  in  the  case  of  sugar.  Even  during  the  injection 
of  considerable  quantities  of  sugar  into  the  portal  vein,  no  difference 
in  percentage  can  be  demonstrated  between  the  blood  of  the  two  sides 
of  the  liver,  although  we  know  that  sugar  is  being  retained  to  form 
glycogen.  For  the  same  reasons,  differences  in  the  percentage  amounts 
of  amino  acids  or  of  urea  are  often  difficult  to  demonstrate  in  the  blood 
entering  and  leaving  the  liver  even  when  we  know  that  large  quantities 
of  them  are  being  added  to  or  removed  from  it. 

Clinical. — Since  the  liver  is  an  important  seat  of  urea  formation,  the 
question  arises  as  to  whether  the  relative  percentage  of  urea  and  am- 
monia in  the  urine  will  become  altered  by  disease  of  the  liver.  Many 
observations  with  this  point  in  view  have  been  undertaken,  but  it  can 
not  be  said  that  the  results  are  very  striking.  In  extreme  destruction, 
such  as  that  produced  by  phosphorus  poisoning,  there  may  indeed  be 
a  great  increase  in  the  relative  amount  of  ammonia  and  a  decrease  in 
that  of  urea.  The  same  is  true  in  acute  yellow  atrophy  of  the  liver,  in 
which  disease  the  nitrogen  excreted  as  ammonia  may  amount  to  as  much 
as  70  per  cent  of  that  excreted  as  urea.  In  milder  forms  of  liver  dis- 
turbance, however,  such  as  cirrhosis,  the  figures  are  much  less  striking. 
When  an  increased  ammonia  excretion  is  observed  in  such  cases,  we 
must  be  cautious  in  drawing  the  conclusion  that  it  is  due  primarily  to 
abolition  of  the  hepatic  function.  It  may  just  as  well  be  caused  by  the 
development  of  acids  in  the  organism  that  require  the  ammonia  for 
their  neutralization.  It  is  significant,  for  example,  that  considerable 
quantities  of  acids  are  produced  in  phosphorus  poisoning. 

Although  the  urea  and  ammonia  excretions  become  altered  by  exten- 
sive destruction  of  liver  tissue,  it  is  a  remarkable  fact  that  very  little  if 
any  change  occurs  in  the  amino  nitrogen,  either  of  the  urine  or  of  the 
blood.  In  experimental  necrosis  of  the  liver  produced  by  chloroform 
or  by  phosphorus,  it  is  only  in  the  latest  stages  of  the  condition  and 
when  it  is  of  the  very  severest  type  that  an  amino-acid  increase  has  been 
found  to  occur  in  the  blood  and  urine.  The  conditions  seem  to  be  some- 
what different  in  man,  abnormally  high  amounts  of  amino  nitrogen  hav- 
ing been  observed  in  the  blood  in  a  considerable  proportion  of  patients 
with  impaired  liver  function.  In  very  severe  cases  of  diabetes,  for  ex- 
ample, figures  that  are  distinctly  higher  than  normal  have  been  observed 
(Van  Slyke,  etc.).  In  eclampsia  the  marked  pathologic  changes  in  the 
liver  might  be  expected  to  be  associated  with  an  upset  in  the  metabo- 
lism of  amino  acids.  Losee  and  Van  Slyke35  have,  however,  recently 
shown  by  the  most  accurate  methods  that  neither  in  the  blood  nor  in  the 
urine  is  any  excess  of  amino  acids  to  be  found  in  this  condition,  although 


THE    METABOLISM    OF   PROTEIN  621 

in  cases  of  pernicious  vomiting  of  pregnancy,  there  was  a  relative  in- 
crease in  the  ammonia  excretion.  We  have  already  seen  that  this 
increase  did  not  bear  any  relationship  to  the  acid-absorbing  power  of 
the  blood  plasma   (see  page  617). 

The  importance  of  the  kidneys  in  removing  the  urea  from,  the  blood 
is  readily  seen  from  the  change  in  the  percentage  of  urea  in  this  fluid 
after  the  partial  or  complete  removal  of  the  kidneys.  Animals  sur- 
vive nephrectomy  for  about  three  days,  and  during  this  time  urea  rapidly 
accumulates  in  the  blood  and  begins  to  make  its  appearance  in  the 
saliva  and  the  intestinal  secretions.  In  man  also  where  the  kidneys 
are  extensively  diseased,  a  similar  accumulation  of  urea  occurs  in  the 
blood,  some  of  the  excess  being  got  rid  of  through  the  sw^eat  and  to  a 
certain  extent  through  the  intestine.  The  importance  of  encouraging 
perspiration  and  a  free  movement  of  the  bowels  in  cases  of  nephritis  is 
thus  indicated.  It  must  not  be  concluded  that  the  accumulation  of 
urea  in  the  organism  is  the  direct  cause  of  the  symptoms.  Urea  itself 
is  comparatively  inert,  and  it  is  generally  believed  that  other  metabolic 
products  with  which  the  urea  runs  parallel  in  amount  are  the  toxic 
agents.  Hewlett  has  found,  however,  that  very  large  injections  of  urea 
do  produce  symptoms  in  animals.34 


CHAPTER  LXX 

THE  METABOLISM  OF  PROTEIN  (Cont'd) 

CREATINE  AND  CREATININE 

Creatine  and  creatinine  are  very  largely  products  of  endogenous  metab- 
olism ;  they  are  mainly  derived  from  chemical  processes  occurring  in 
the  tissues  although  some  of  the  creatine  and  creatinine  present  in  the 
food  may  appear  as  creatine  in  the  urine. 

Essential  Chemical  Facts 

Before  we  proceed  further  with  a  discussion  of  the  metabolism  of 
these  important  substances,  it  will  be  necessary  to  refer  briefly  to  some 
points  in  their  chemistry.  The  simpler  of  the  two  bodies  is  creatine, 
which  is  methyl-guanidine-acetic  acid ;  creatinine  is  its  anhydrid,  being 
formed  from  creatine  by  the  removal  of  a  molecule  of  water,  so  that  the 
NH2  groups  become  joined  together  in  the  same  way  as  they  do  in  the 
formation  of  peptides  from  amino  acids  (page  599).  The  relationships 
are  illustrated  in  the  following  formulas: 

(methyl) 
CH3— N 

/    \ 
/  CH^COOH 

NH  =  C  -IL,0  = 

\  (acetic  acid) 

\ 
(guanidine)      NH2 

(creatine) 

CH,  -  N  -  CH  -  CO 


NHz=C 

\      I 

NH 

(creatinine) 

It  should  be  noted  that  guanidine  is  closely  related  to  urea 
NH2 

/ 

(0=C  ),  and  that  when  creatinine  is  formed  from  creatine  a  ring 

\ 

NH2 

622 


Tin;    METABOLISM    OF   PROTEIN  023 

formation  occurs,  giving  what  may  l>o  regarded  as  an  imidazole  deriva- 
tive (sec  page  li04).  Creatine  is  also  related  to  one  of  the  important 
diamino  acids,  arginine,  since  both  contain  guanidine  radicles, 

NIT., 

/ 

(NTI=C  L  and  to  bistidine  and  the  purines  (see  page  634),  hoth 

\ 
NIL 

of  which  contain  the  imidazole  ring.  The  close  relationship  which 
creatine  bears  to  urea  is  illustrated  by  the  fact  that  urea  is  formed 
when  creatine  is  subjected  to  the  action  of  boiling  barium  hydrate.  When 
it  is  oxidized  by  means  of  potassium  permanganate,  urea  is  also  formed, 
the  remainder  of  the   molecule,  more   or  less  intact,  being  split  off  as 

NH-CH3 

/ 

methyl-amino-acetic  acid  (Clio  ),  also  known  as  sarcosine. 

\ 

COOH 

The  conversion  of  creatine  to  creatinine  goes  on  slowly  in  aqueous 
solutions,  but  is  much  accelerated  by  heating  with  acid.  Heated  in  an 
autoclave  at  a  temperature  of  117°  C.  for  thirty  minutes,  with  half  nor- 
mal hydrochloric  acid,  the  creatine  goes  over  almost  quantitatively  into 
creatinine.  It  will  be  noted  that  the  creatinine  ring  is  partly  oxidized. 
This  renders  it  unstable,  so  that  creatinine  in  the  presence  of  alkalies 
has  the  power  of  reducing  metallic  oxides.  Like  glucose  it  can  reduce 
alkaline  solutions  of  copper,  silver  and  mercuric  salts;  it  also  reduces 
picric  acid  in  weakly  alkaline  solution  to  picramic  acid,  which,  being  red, 
furnishes  us  with  a  solution  the  strength  of  which  can  be  estimated 
colorimetrically. 

Quantitative  Estimation. — Although  the  presence  of  creatinine  in  the 
urine  has  been  known  for  many  years,  there  being  from  1  to  2  grams  of 
it  in  the  twenty-four-hour  urine,  little  progress  was  made  in  the  study 
of  its  metabolism  because  of  the  absence  of  a  reliable  method  for  its 
estimation.  The  elaboration  by  Folin  of  a  colorimetric  quantitative 
method  for  creatinine,  depending  on  the  reduction  of  picric  acid,  has 
furnished  the  starting  point  for  the  modern  work  which  has  been  done. 
To  estimate  the  creatine  by  this  method,  it  is  usual  to  proceed  as  fol- 
lows: The  creatinine  content  is  first  of  all  determined,  another  portion 
of  urine  being  then  heated  with  acid  in  the  autoclave  until  all  of  its 
creatine  has  been  converted  into  creatinine.  A  second  determination  of 
creatinine  is  then  made,  and  the  difference  between  the  two  is  calculated 
as  creatine. 


624  METABOLISM 

It  should  be  pointed  out  that,  since  the  creatine  is  estimated  by  an 
indirect  method,  there  are  considerable  chances  for  inaccuracy.  Indeed, 
it  has  been  shown  that  errors  may  have  been  incurred  in  some  of  the 
recent  work  on  account  of  the  fact  that  when  acetoacetic  acid  is  present 
in  the  urine  it  prevents  the  creatinine  from  developing  its  full  reducing 
power  on  picric  acid  in  the  cold,  so  that  when  subsequently  the  urine  is 
heated  with  acid  for  the  purpose  of  converting  the  creatine  into  creati- 
nine, the  destruction  of  acetoacetic  acid  allows  the  reducing  power  of  the 
creatinine  to  develop  to  full  intensity.  It  is  obvious  that  this  would  make 
it  appear  as  if  creatine  had  been  converted  into  creatinine.  It  is  par- 
ticularly in  the  urine  of  diabetic  patients,  in  which  acetoacetic  acid  is 
present  that  mistakes  are  likely  to  be  made. 

Metabolism 

When  we  come  to  consider  the  metabolism  of  creatine  and  creatinine, 
we  find  that  there  are  remarkably  few  facts  definitely  known  concerning 
it.  The  average  amount  excreted  daily,  expressed  as  the  number  of  milli- 
grams of  creatinine  in  twenty-four  hours  per  kilogram  body  weight, 
is  known  as  the  creatinine  coefficient  (Shaffer).36  For  a  lean  person  this 
is  about  25  mg. ;  for  a  corpulent  person,  about  20  mg.,  the  difference  in- 
dicating that  muscle  mass,  and  not  body  weight,  is  the  important  factor 
determining  the  coefficient.  Further  evidence  that  this  relationship  ex- 
ists is  furnished  by  the  fact  that  in  the  muscular  atrophies  creatine  ex- 
cretion is  distinctly  below  normal.  It  must  be  the  mass  of  the  muscles 
rather  than  their  activities  that  is  the  determining  factor,  for  the  creatine 
excretion  does  not  become  increased  by  muscular  exercise. 

Influence  of  Food,  Age,  and  Sex.— Although  creatine  and  creatinine  are 
endogenous  metabolites,  it  must  be  remembered  that,  under  ordinary 
dietetic  conditions,  a  part  of  each  is  derived  from  these  substances  pres- 
ent in  the  food.  It  is  important  therefore  to  consider  the  conditions 
under  which  the  creatine  and  creatinine  in  the  food  appear  in  the  urine. 
Regarding  creatinine,  it  is  pretty  well  established  that  practically  all 
that  is  taken  with  the  food  reappears  as  creatinine  in  the  urine.  Shaffer 
has,  for  example,  succeeded  in  recovering  76  per  cent  of  ingested  creat- 
inine in  the  urine  excreted  during  twenty-one  hours  following  the  in- 
gestion of  0.7  gm.  creatinine. 

The  conditions  for  the  excretion  of  creatine  are  more  complex.  It  is 
present  in  the  urine  of  children  in  considerable  amount,  but  in  that  of 
adults  only  as  traces.  In  the  first  years  of  life  the  creatine  in  boys' 
urine  may  amount  to  one-half  of  the  total  creatine  and  creatinine,  but 
it  becomes   gradually  less   and  practically  disappears   at   about   seven 


THE   METABOLISM   OP   PROTl  l\  625 

years  of  age.  Oirls,  on  the  other  hand,  continue  to  excrete  creatine  until 
about  puberty,  after  which,  although  ordinarily  absent,  it  reappears  in 
the  urine  at  each  monthly  sexual  cycle,  and  is  present  during  pregnancy 
and  for  some  days  after  delivery.  Feeding  creatine  to  children  causes 
it  to  appear  in  the  urine,  accompanied  usually  by  a  slight  increase  in 
the  creatinine.  The  same  results  can  be  observed  in  women  during  the 
monthly  periods,  when  as  much  as  0.1  gm.  may  be  present,  and  during 
pregnancy.  Creatine  is  also  present  in  the  urine  of  most  if  not  all  of 
the  other  mammalia.  Some  of  these  facts  are  shown  in  the  following 
table : 


AGE 

CREATIXIXE-X 

CREATIXE-X  EXCRETED 

IX 

24-HR.  URINE 

•  > 

0.025 

0.023 

3 

0.057 

0.022 

Boys-i 

5 

S 

0.112 
0.163 

0.025 
0.0 

11 

0.157 

0.0 

15 

0.378 

0.0 

'    5 

0.060 

0.005 

6 

0.032 

0.003 

Girls  I 

7 

0.157 

0.066 

10 

0.147 

0.020 

12 

0.201 

0.011 

(From  Mathews.) 

When  creatine  is  given  to  an  animal  that  has  been  kept  in  a  starved 
condition,  most  of  it  seems  to  disappear.  It  can  not  be  recovered  in  the 
urine  either  as  creatine  or  as  any  other  nitrogenous  metabolite.  It  seems 
to  functionate  more  as  a  food  than  as  a  useless  substance.  The  possi- 
bility that  some  of  it  can  be  destroyed  by  the  intestinal  bacteria  being 
admitted,  there  is  nevertheless  some  justification  for  the  view  that  the 
creatine  finds  a  useful  function  in  the  anabolic  process  of  the  muscles. 

Influence  of  Complete  and  Partial  Starvation. — Although,  as  we  have 
seen,  the  creatinine  excretion  remains  constant  when  the  amount  of  pro- 
tein in  the  diet  is  greatly  reduced,  yet  it  does  not  remain  constant  during 
complete  fasting  or  when  carbohydrates  are  entirely  withheld  from  the 
diet.  In  fasting  it  has  been  found  that  creatine  appears  in  place  of  the 
creatinine  which  has  disappeared,  so  that  if  both  creatine  and  creatinine 
are  determined,  very  little  if  any  diminution  will  be  found  to  have  oc- 
curred. Fasting,  therefore,  causes  the  adult  creatine  and  creatinine 
metabolism  to  become  like  the  juvenile  metabolism.  As  pointed  out  by 
Mathews,  it  would  be  interesting  in  the  light  of  this  observation  to  see 
whether  other  substances,  passed  in  the  urine  of  young  animals  but  ab- 
sent in  that  of  the  adult,  would  reappear  in  the  urine  when  the  animals 
were  made  to  fast.  In  the  case  of  man,  for  instance,  allantoin  would  be 
worth  investigating  in  this  regard  (page  641). 


626  METABOLISM 

A  similar  replacement  of  some  of  the  creatinine  l)y  creatine  appears 
when  carbohydrate  is  entirely  -withheld  from  the  diet,  or  in  diabetic 
animals,  either  in  the  disease  diabetes  mellitns  in  man  or  in  the  experi- 
mental condition  induced  in  animals  by  giving  phlorhizin.  Unfortu- 
nately, in  a  considerable  part  of  the  work  that  has  been  done  on  this 
phase  of  the  subject  a  method  of  estimation  was  employed  which  did  not 
take  sufficiently  into  account  the  influence  of  acetoacetic  acid  on  the 
creatine  estimation;  but  even  after  allowing  for  this  possible  source  of 
error,  there  can  be  no  doubt  that  creatine  appears  in  the  urine  when 
carbohydrates  are  improperly  metabolized.  If  carbohydrates  are  given 
to  a  starving  animal,  for  example,  the  creatine  is  replaced  in  its  urine  by 
creatinine,  although  this  will  not  occur  when  either  protein  or  fat  is  fed. 
The  general  conclusion  which  may  be  drawn  from  these  observations  is 
that  carbohydrates  in  some  way  are  required  for  the  proper  conversion 
of  creatine  into  creatinine  in  the  animal  body  (Cathcart)37. 

Origin  of  Creatine  and  Creatinine 

Notwithstanding  the  amount  of  excellent  work  that  has  recently  been 
done  on  the  metabolism  of  creatine  and  creatinine,  we  know  very  little 
indeed  regarding  the  origin  of  these  bodies  in  the  animal  organism.  It 
would  be  profitless  to  discuss  this  problem  to  any  great  extent,  but  a 
few  of  the  most  important  facts  so  far  established  may  be  of  interest  and 
of  value.  The  first  step  in  attacking  such  a  problem  is  to  compare  the 
amounts  present  in  the  various  organs  and  tissues,  in  the  blood,  and  in 
the  excreta.  Of  the  approximately  120  grams  of  creatine  and  creatinine 
in  the  body  of  an  average  adult,  a  very  large  proportion  is  in  the  muscles, 
the  voluntary  muscles  containing  the  largest  percentage,  the  heart  con- 
taining a  medium  percentage,  and  the  involuntary  (intestinal)  muscles 
containing  relatively  a  small  amount  (Myers  and  Fine)38.  Next  to  the 
skeletal  muscles,  and  containing  more  than  the  involuntary  mus- 
cles, come  the  testis  and  brain.  The  liver,  pancreas,  thyroid,  kidneys, 
spleen,  etc.,  contain  traces,  the  smallest  amount  of  all  being  found  in  the 
blood. 

In  all  these  places  by  far  the  greatest  proportion  of  the  total  creatine- 
creatinine  exists  as  creatine,  which  is  exactly  the  reverse  of  the  condi- 
tion obtaining  in  the  urine  of  adults,  where  practically  all  is  excreted  as 
creatinine.  The  close  chemical  relationship  between  creatine  and  creat- 
inine, considered  along  with  the  above  facts  regarding  their  quantitative 
distribution  in  the  body,  indicates  that  the  creatinine  of  the  urine  is  de- 
rived from  the  creatine  of  the  tissues.  The  question  is,  IIoic  does  the 
creatine  come  to  be  converted  into  en  atinine?     Such  a  transformation  is 


THE    METABOLISM    OP    PROTEIN  627 

probably  effected  by  many  of  the  tissues  of  the  body  and  certainly  by 

the  bl 1,  the  active  agency  in  all  cases  being  no  doubt  an  enzyme.    That 

the  blood  contains  such  an  enzyme  is  indicated  by  the  fact  that  creatine 
is  transformed  to  creatinine  by  blood  serum  more  quickly  than  it  is 
when  merely  dissolved  in  water.  Even  healed  blood  serum  poss< 
some  of  this  power.  The  liver  also  probably  brings  about  the  transfor- 
mation, as  has  been  shown  by  perfusion  experiments,  and  by  the  fact 
that  in  cases  of  phosphorus  or  hydrazine  poisoning  creatine  displaces 
creatinine  in  the  urine. 

The  problem  therefore  narrows  itself  down  to  the  question  of  the 
origin  of  creatine.  In  the  light  of  chemical  knowledge  there  are  several 
precursors  from  which  creatine  might  be  formed.  One,  for  example,  is 
arginine,  which  it  will  be  remembered  is  guanidine-amino-valerianic  acid 
(see  page  605).  By  oxidation  this  might  become  changed  into  gnani- 
dine-amino-acetie  acid,  which  by  methylation  would  then  be  changed  into 
creatine.  That  such  a  process  of  methylation  may  actually  occur  in  the 
animal  body  is  definitely  known,  for  it  happens  when  such  substances  as 
pyridine  or  naphthalene  are  given  with  the  food.  They  appear  in  the 
urine  as  methyl  derivatives.  The  possibility  of  the  derivation  of  creatine 
from  arginine  is  not,  however,  borne  out  by  the  result  of  the  injection  of 
arginine.  for  such  injection  does  not  increase  the  creatinine  in  the  urine. 
The  closely  related  substance,  guanidine-acetic  acid,  when  fed  to  animals 
(rabbits)  does  cause  a  slight  increase  in  the  excretion  of  creatine  (Jaffe), 
and  also,  it  is  said,  an  increase  in  the  creatine  content  of  the  muscle. 
Even  in  this  case,  however,  by  far  the  largest  proportion  of  the  admin- 
istered guanidine-acetic  acid  is  excreted  in  the  urine  unchanged. 

The  large  percentage  of  creatine  in  muscle  tissue  leads  one  to  expect 
that  some  relationship  must  exist  between  muscular  metabolism  and  the 
amount  of  creatine  present  either  as  such  in  the  muscles  or  as  creatinine 
in  the  urine.  Regarding  the  latter  point  it  is  definitely  established  that 
muscular  exercise  leads  to  no  increase  in  the  creatinine  excretion,  al- 
though it  is  said  that  an  increase  occurs  following  a  tonic  contraction 
of  the  muscles.  With  regard  to  the  creatinine  in  the  muscles,  no  definite 
results  indicating  that  muscular  metabolism  changes  its  amount  are  on 
record.  In  the  light  of  the  fact  already  stated  regarding  the  presence 
of  creatine  in  other  organs  than  the  muscles,  it  seems  probable  that  the 
substance  has  really  little  to  do  with  muscular  contraction  as  such,  but 
rather  is  concerned  in  some  way  in  the  formative  metabolism  of  the  cell, 
with  its  general  growth  or  maintenance.  Indeed,  it  is  a  question  whether 
creatine  is  an  actual  constituent  of  the  living  tissue.  It  may  rather,  as 
has  been  suggested  by  Polin,  be  a  postmortem  product,  represented  dur- 
ing life  bv  creatinine. 


628  METABOLISM 

Creatine  appears  in  the  urine  in  phosphorus  poisoning,  in  carcinoma  of 
the  liver  and  during  postpartum  involution  of  the  uterus.  It  is  not  de- 
rived from  the  disappearing  uterine  muscle,  however,  for  creatinuria  also 
occurs  after  cesarean  section  with  removal  of  the  uterus.  Creatine 
elimination  is  not  an  index  of  cellular  destruction,  for  it  has  been  found 
large  in  a  dog  injected  with  phlorhizin  and  maintained  in  constant  weight 
by  feeding  with  washed  meat  (S.  R.  Benedict).  Muscular  fatigue  also 
leaves  the  creatine  content  of  muscle  unchanged.  In  late  stages  of 
nephritis,  creatinine  accumulates  in  the  blood  and  serves  as  an  index  of 
the  gravity  of  the  condition  (page  651). 


CHAPTER  LXXI 

THE  METABOLISM  OF  PROTEIN  (Cont'd) 

UNDETERMINED  NITROGEN  AND  DETOXICATION 
COMPOUNDS 

In  the  present  chapter  we  shall  refer  briefly  to  the  groups  of  urinary 
substances  styled  undetermined  nitrogenous  compounds  arid  to  the  com- 
pounds that  are  excreted  in  the  urine  as  the  result  of  the  combination  in 
the  body  of  certain  toxic  bodies  with  chemical  substances  that  render 
them  harmless  (detoxication  compounds). 

Undetermined  Nitrogen 

Included  under  undetermined  nitrogen  are  amino  acids,  peptides  and 
basic  substances.  The  amount  of  amino  acids  and  peptides  in  normal 
urine  is  very  small  but  may  become  considerable  in  disease,  especially 
of  the  liver,  when  leucine  and  tyrosine  may  appear.  The  presence  of 
traces  of  amino  acid  and  peptone  in  normal  urine  is  to  be  expected, 
for  although  the  actual  concentration  of  amino  acids  in  the  blood  is 
never  very  great,  a  certain  leakage  of  amino  acids  must  occur  into  the 
urine. 

The  peptide  is  sometimes  known  as  oxyproteic  acid.  It  becomes  dis- 
tinctly increased  in  phosphorus  poisoning  and  in  such  conditions  as  are 
accompanied  by  excessive  protein  metabolism.  The  basic  constituents 
include  such  substances  as  trimethylamine,  ethylamine,  putrescine  and 
cadaverine  (page  502),  and  there  are  probably  many  more  of  a  similar 
nature.  Many  of  these  substances  are  similar  to  the  so-called  ptomaines 
found  in  meat,  etc.,  and  they  have  been  called  the  ptomaines  of  urine, 
from  which  they  can  be  isolated  by  rendering  the  urine  alkaline  and 
shaking  out  Math  ether.  It  is  probably  to  the  presence  of  these  sub- 
stances that  urine  mainly  owes  its  toxic  action. 

The  Detoxication  Compounds 

Certain  nocuous  substances  are  produced  in  the  intestine  during  the 
digestive  process  (see  page  501),  and  others  may  result  from  the  meta- 
bolic processes  in  the  tissues.  To  guard  against  the  harmful  action  of 
these  substances  on  the  organism,  they  become  detoxicated  in  various 

629 


6-30  METABOLISM 

ways,  mainly  by  forming  inert  compounds  with  other  substances,  par- 
ticularly with  glycocoll,  sulphuric  acid  or  glycuronic  acid.  The  com- 
pound thus  formed  is  then  excreted  in  the  urine. 

Hippuric  Acid. — Glycocoll  is  used  mainly  to  detoxicate  the  benzoic 
acid  which  results  from  the  oxidation  of  the  aromatic  substances  pres- 
ent in  large  quantities  in  vegetable  food  and  fruit  (particularly  in  cran- 
berries). Some  benzoic  acid  may  also  be  produced  by  the  breakdown 
of  the  aromatic  group  of  the  protein  molecule;  phenylalanine,  for  ex- 
ample, gives  rise  to  benzoic  acid  by  bacterial  decomposition.  The  com- 
pound formed  is  hippuric  acid,  this  name  indicating  that  it  is  present  in 
large  quantities  in  the  urine  of  the  horse,  as  it  is  also  in  the  urine  of 
all  herbivorous  animals. 

Hippuric  acid  is  benzoyl-glycine  (C6H5.C0.NH.CH2C00H),  and  it 
can  readily  be  produced  in  the  laboratory  by  bringing  together  benzoyl 
chloride  with  glycocoll,  thus: 


a,H,.CO  iCl  +  Hj  HN.CH2COOH  =  CcH5CO.NH.CH2COOH  +  HCl. 

(benzoyl  chloride)       (glycocoll)  (hippuric  acid) 

Under  ordinary  dietetic  conditions  only  a  trace  of  hippuric  acid  is 
present  in  the  urine  of  man,  but  much  larger  quantities,  2  grams  a  day 
for  example,  may  appear  when  the  diet  contains,  a  large  proportion  of 
fruit  or  vegetables.  It  is  not  known  to  undergo  any  characteristic  varia- 
tions in  disease.  The  benzoic  acid  -which  is  contained  in  certain  canned 
foods  as  preservative  also  combines  in  the  body  with  glycocoll,  so  that 
any  toxic  effect  which  it  might  produce  is  practically  negligible.  There 
is  certainly  no  very  evident  reason  why  canned  foods  containing  benzoic 
acid  should  be  tabooed,  for  in  so  far  as  the  berzoic  acid  is  concerned,  they 
can  be  no  more  toxic  than  a  diet  composed  largely  of  vegetables  and 
fruit. 

This  detoxication  of  benzoic  acid  requires  the  presence  in  the  organ- 
ism of  a  constant  supply  of  glycocoll,  which,  it  will  be  recalled, 
is  the  lowest  in  the  series  of  amino  acids,  being  aminoacetic  acid 
(CH2NH2COOH).  It  is  present  in  greatest  amount  in  the  protein  of  the 
connective  tissues.  It  is  said,  however,  that  not  more  than  from  2  to 
3.5  per  cent  of  glycocoll  is  available  in  the  proteins  of  the  body.  Al- 
though this  amount  of  glycocoll  would  amply  suffice  to  detoxicate  the 
benzoic  acid  produced  by  the  metabolism  of  the  food  in  carnivora,  it 
is  quite  inadequate  for  this  purpose  in  the  case  of  herbivora,  and  the 
question  naturally  presents  itself  as  to  Avhere  the  glycocoll  in  these 
animals  comes  from.  It  is  said,  for  example,  that  of  the  total  nitrogen 
excretion  in  herbivora  50  per  cent  may  appear  as  glycocoll  under  cer- 
tain conditions.     These  facts  indicate  that  the  organism  is  capable  of 


THE    METABOLISM    OF    PROTEIN  631 

producing  new  glycocoll  for  itself,  and  it  is  interesting  to  consider  how 
this  glycocoll  may  be  derived.  A  very  probable  source  is  by  synthesis 
between  ammonia  and  glyoxylic  acid  i<'II<».  COOH).  That  glyoxylic  acid 
or  its  aldehyde,  glyoxal,  is  readily  produced  during  metabolism  from  car- 
bohydrates and  thai  ammonia  is  always  available  would  seem  to  lend 

s support    to  this  view    (see   page   665).     The  synthesis  of  glycocoll 

from  glyoxal  and  ammonia  occurs  thus: 

H.COCHO     NH,  =  CH2NH2C00H. 
glyoxal)  (glycocoll) 

The  linking  up  of  glycocoll  with  benzoic  acid  occurs  in  the  kidney. 
If  the  kidney  is  removed  from  the  circulation  in  the  majority  of  animals 
that  produce  hippuric  acid  in  large  amount — the  rabbit  being  an  excep- 
tion— no  hippuric  acid  will  accumulate  in  the  blood.  On  the  other  hand, 
an  isolated  perfused  preparation  of  the  kidney  produces  hippuric  acid 
provided  benzoic  acid  is  added  to  the  perfusion  fluid,  and  the  latter  also 
contains  an  abundance  of  oxygen,  which  is  best  secured  by  using  de- 
fibrinated  arterialized  blood  instead  of  artificial  serum  (Locke's  solu- 
tion). The  necessity  of  a  plentiful  supply  of  oxygen  is  further  shown 
by  the  fact  that,  if  the  hemoglobin  of  the  blood  is  rendered  incapable 
of  carrying  02  by  bubbling  carbon  monoxide  gas  through  it,  no  synthe- 
sis of  hippuric  acid  will  result  from  perfusing  the  blood  through  the 
kidney.  The  actual  chemical  process  by  which  the  synthesis  occurs  (de- 
hydration) is  similar  to  that  by  which  polypeptides  are  formed  by  the 
union  of  amino  acids,  or  creatinine  from  creatine. 


(c6h5co  ;oh  +  h;  hnch2cooh). 

Glycocoll  may  be  used  for  detoxicating  other  substances  than  benzoic 
acid,  particularly  cholic  acid,  forming  the  glycocholic  acid  of  the  bile 
(see  page  494)  and  phenylacetic  acid.  In  birds  the  benzoic  acid  be- 
comes combined  with  diamino-valerianic  acid  or  ornithine  (NH2  -  CH2  - 
CH2-CH2-CTI-XII.2-COOH)  in  place  of  glycocoll,  so  that  in  the  urine 
of  these  animals  in  place  of  hippuric  acid  a  compound  called  ornithuric 
acid  occurs. 

It  is  of  importance  to  point  out  here  that  this  pairing  of  aromatic  toxic 
substances  with  certain  of  the  metabolic  products  of  the  organism  has 
frequently  been  found  an  excellent  experimental  method  for  demon- 
strating the  presence  of  intermediary  metabolic  substances  that  other- 
wise would  not  have  appeared  in  the  excreta.  These  substances  are 
thus  diverted  from  their  normal  course  in  metabolism  so  as  to  form 
neutralization  or  detoxication  compounds.    Glycuronic  acid  is  an  example. 


632  METABOLISM 

Ethereal  Sulphates  and  Glycuronates. — The  other  substances  used  for 
detoxication  purposes  are  sulphuric  and  glycuronic  acids.  Phenol,  and 
its  derivative  cresol,  after  being  absorbed  from  the  intestine,  in  the 
contents  of  which  they  are  produced  by  the  bacterial  decomposition  of 
protein  (see  page  501)  become  combined  in  the  body,  probably  in  the 
liver,  with  sulphuric  acid  or  with  glycuronic  acid  to  form  the  sulphate 
or  glycuronate.  The  aromatic  sulphate  further  combines  with  potassium 
to  form  the  so-called  ethereal  sulphates,  as  which  the  substance  is  excreted 
in  the  urine.  A  small  amount  of  phenol  may  however  appear  in  the 
urine  unchanged.  As  we  have  already  seen,  the  sources  of  the  phenol 
in  the  intestine  are  tyrosine  and  phenylalanine  (see  page  530),  and 
since  these  amino  acids  are  also  present  in  the  tissues,  it  might  be  sup- 
posed that  some  of  the  phenol  sulphate  of  potassium  present  in  the 
urine  could  come  from  the  tissues.  It  is  usually  assumed  that,  however, 
derivation  from  the  tissues  does  not  occur. 

Another  ethereal  sulphate  is  indoxyl  sulphate  of  potassium.,  which  re- 
sults from  the  absorption  into  the  blood  of  the  indole  and  skatole  pro- 
duced by  intestinal  putrefaction  from  tryptophane  (see  page  502). 
Immediately  after  absorption  indole  is  oxidized  to  indoxyl,  which  then 
combines  with  sulphuric  acid  and  with  potassium  to  form  indoxyl  sul- 
phate of  potassium,  which  is  the  well-known  indican  of  the  urine.  As 
in  the  case  of  phenol  sulphate  of  potassium,  none  of  the  urinary  indican 
seems  to  come  from  the  normal  metabolism  (of  the  tryptophane)  of  the 
tissue  proteins.  It  is  a  much  more  reliable  indicator  than  phenol  sul- 
phate of  potassium  of  the  extent  of  intestinal  putrefaction,  but  it  also 
becomes  increased  in  amount  during  putrefaction  in  the '  body  itself, 
as  for  example  in  abscess  formation. 

The  amount  of  indican  in  the  urine  may  be  roughly  gauged  by  oxi- 
dizing the  urine  by  means  of  hypochlorite  and  then  shaking  out  with 
chloroform.  If  the  resulting  extract  is  more  than  light  blue  in  color, 
it  indicates  excessive  putrefaction.  A  negative  test  does  not  neces- 
sarily mean  that  intestinal  putrefaction  is  absent,  but  a  marked  positive 
test  always  indicates  that  it  is  occurring.  Skatole,  the  methyl  deriva- 
tive of  indole,  may  undergo  similar  processes  and  appear  in  the  urine 
during  excessive  intestinal  putrefaction.  Its  presence  in  the  blood  some- 
times confers  on  the  breath  a  distinct  fecal  odor,  for  this  body,  as  its 
name  indicates,  is  that  to  which  the  odor  of  the  feces  is  due. 

Glycuronic  acid,  the  other  substance  used  for  detoxication  processes, 
is  of  the  nature  of  a  dextrose  molecule  with  the  one  end-group  oxidized 
to  carboxyl  (CHO  -  (CHOH)4  -  COOH).  It  is  probably  produced  under 
normal  processes  of  metabolism  in  the  animal  body,  but  is  destroyed 
unless  when  such  poisonous  substances  as  camphor,  chloral  hydrate  or 


THE    METABOLISM    OF    PROTEIN  633 

certain  aromatic  alcohols  are  given,  -when  it  is  used  for  the  purpose  of 
detoxicating  them.  The  resulting  glycuronates  have  reducing  powers 
and  may  be  confused  with  glucose  when  present  in  large  amount.  Gly- 
curonates may  be  distinguished  from  glucose  in  the  urine  (1)  because 
they  are  levorotatory,  and  (2)  because  they  do  not  ferment.  The  free 
acid  itself,  however,  is  dextrorotatory. 


CHAPTER  LXXII 
URIC  ACID  AND  THE  PURINE  BODIES 

Introductory. — The  participation  by  highly  trained  organic  chemists 
in  the  investigation  of  biochemical  problems  has  brought  our  knowledge 
of  the  history  of  the  purine  substances  in  the  animal  body  from  a  state 
of  chaos  and  guesswork  to  one  of  system  and  scientific  accuracy.  The 
peculiar  solubility  reactions  of  uric  acid  and  its  salts  and  the  discovery 
of  urates  in  gouty  deposits  served  to  make  uric  acid  metabolism  one  of 
the  earliest  research  problems  in  both  the  medical  clinic  and  the  bio- 
chemical laboratory,  but  the  earlier  results  were  practically  valueless, 
partly  because  they  were  inaccurate  and  partly  because  their  interpretation 
was  impossible  in  the  absence  of  even  the  most  elementary  facts  concerning 
the  chemistry  of  uric  acid. 

Before  any  real  progress  was  possible,  a  clean  sweep  had  to  be  made 
of  all  the  old  speculations  and  hypotheses,  such  as  that  dignified  by  the 
high-sounding  name  of  "uric-acid  diathesis,"  and  a  foundation  of  ac- 
curate chemical  knowledge  established.  This  foundation  is  now  wonder- 
fully complete,  and  a  superstructure  of  biochemical  fact  is  already 
beginning  to  groAV  upon  it.  In  the  present  chapter  we  shall  examine 
some  of  the  most  important  contributions  that  have  made  this  progress 
possible. 

As  in  the  study  of  any  other  problem  of  metabolism,  we  must,  however, 
make  ourselves  familiar  with  the  main  facts  concerning  the  chemistry 
of  the  purine  bodies  and  of  the  tissue  constituents  into  the  composition 
of  which  they  enter,  before  proceeding  to  the  more  strictly  biological 
aspect  of  the  subject. 

The  Chemical  Nature  of  the  Purines 

By  an  examination  of  the  empiric  formulas  of  the  purines  of  biochem- 
ical interest,  it  will  be  observed  that  they  are  all  derivatives  of  a  sub- 
stance purine,  which  although  in  itself  of  no  importance  is  interesting, 
since  it  serves  as  the  basic  substance  from  which  the  others  are  derived. 
The  list  is  as  follows: 

1  Purine 
bases. 


Purine 

.     C5H,N4 

Hypoxanthine 

.     C5H4N40 

Monoxypurine 

Adenine 

.     CrH,N4.NH, 

Amino-purine 

Xanthine     . 

.    <Xh4n4o., 

Dioxypurine 

Guanine 

.     C,H3N4O.NH., 

Amino-oxypurine 

Uric  acid     . 

.     C6H4N403 

Trioxypurine 

634 

URIC   ACID    AM)   THE   PUEINE   BODIES  635 

The  first  oxidation  producl  of  purine  is  hypoxanthine,  which  has 
long  been  known  as  a  constituenl  of  meat  extract.  Adenine,  the  amino 
derivative  of  hypoxanthine,  occurs  in  combination  with  other  substances 
in  the  nuclear  material.  The  second  oxidation  product  is  xanthine  and 
its  amino  derivative,  guanine.  They  occur  in  the  same  places  as  hypo- 
xanthine and  adenine.  The  highest  oxidation  product  of  all  is  the  well- 
known  urinary  constituent,  uric  acid,  which  may  therefore  be  chemically 
designated  as  trioxypurine.  In  addition  to  the  purines  of  animal  origin, 
there  are  also  certain  ones  of  vegetable  origin — the  methyl  purines,  which 
exist  as  the  alkaloids  of  tea  and  coffee — namely,  caffeine,  theobromine, 
and  theine. 

To  understand  the  chemical  structure  of  this  group  of  substances, 
it  is  perhaps  simplest  to  start  with  that  of  uric  acid.  This  consists 
essentially  of  two  urea  molecules  linked  together  by  a  central  chain  of 
three  carbon  atoms,  as  will  be  evident  from  the  accompanying  structural 
formula: 


H 

N-CO 

1 
C 

1 
>C    C  -  NH 

1 
i 

1!        \ 

CO 

II 

II      / 

N-C-NH 

(urea)       (urea) 

(cc 

>ntral  chain) 

This  structure  can  be  shown  by  methods  both  of  decomposition  and 
of  synthesis.  When  uric  acid  is  decomposed  by  oxidizing  it  with  nitric 
acid,  it  yields  urea  and  a  residue  called  alloxan ;  or  it  can  be  synthesized 
from  urea  and  trichlorlactamide,  a  derivative  of  lactic  acid,  which  it 
will  be  remembered  contains  three  carbon  atoms.  The  changes  involved 
in  this  synthesis  will  be  made  clear  by 'examination  of  the  accompanying 
structural  formula,  in  which  the  manner  of  production  of  the  by- 
products of  the  reaction  (NH3,  H20  and  HC1)  are  shown  by  dotted  lines: 


NH.  |  H  NH,  :  -  C  =  O 

/  ' "'     ! 

/  I 

/  I      

/  !   H    !-C       !   OH  H    |     NH 

co  :      :   ii    \ 

\  !  CI  •    ||  CO 

\  \       / 

\  C-    i    CI  H     I     NH      (urea) 

\  /        

(urea)      NH.  !     II  CI     | 

(trichlorlactamide) 


636 


METABOLISM 


By  milder  oxidation  by  means   of  potassium   permanganate   in  the 
cold,  uric  acid  becomes  quantitatively  converted  to  allantoin: 

C5H4N403  +  H20  +  0  =  C4HGN403  +  C02. 
(uric  acid)  (allantoin) 

The  importance  of  this  transformation  lies  in  the  fact  that  in  most 
animals,  man  and  the  higher  apes  being  exceptions,  uric  acid  is  thus 
decomposed  in  the  animal  body.  The  structural  formulas  for  the  other 
purine  bodies  in  relationship  with  those  of  purine  and  uric  acid  are  given 
below. 

Purine  itself  has  the  following  structural  formula: 


in    Cs  H 


H2-C 


C5-NH* 
II  \ 


Cs-H 


II       II  // 

3N  -  CM  -  N9 

(For  convenience  of  description  the  atoms  in  purine  are  numbered  as  shown.) 


HN-C=0 


H-  C     C-NH 


N-C 


N 


\ 
( 

/ 


C-H 


(hypoxanthine)        (6-oxypurine) 
N  =  C  -  NH, 


H- C     C-NH 


HN-C=0 

I       I 
O  =  C      C-NH 

I        II 
HN - C -     N 

(xanthine) 

HN-C=0 

I        I 
H,N  =  C      C-NH 


/ 


C-H 


(2-6-oxypurine) 


N-C-    N' 


\ 
( 

/ 


C-H 


\ 


N-C-    N 


/ 


C-H 


(adenine)      (6-amino-purine)      (guanine) 

HN-CO 

I  I 

OC       C  -  NH 


(2-amino-6-oxypurine) 


\ 


CO 


/ 


HN-  C  -KH 

Urie  acid   (2-6-8-trioxypurine) 

The  substances  with  which  the  purine  bases  are  most  closely  related 
are  the  pyrimidine  bases.    Three  of  these  are  known: 

cytosine   (  N  =  C-NH,        and   uracil    (NH-CO 

I  I  I 

CO     CH  CO      CH 

I        II  I         II 

NH-CH      );  NH-CH);  NH-CH). 


thymine     (NH  -  CO 

I       ! 

CO      C.CH, 


DBIC   ACID   AND  THE   Imkixi:   BODIES  637 

From  an  examination  of  the  structural  formulas,  it  will  be  seen  that 
they  are  more  or  less  related  to  purine  (having  one  of  the  urea  radicles 
omitted),  although  it  can  scarcely  be  doubted  that  they  exist  as  separate 
constituents  of  the  nucleic  acid  group  in  the  animal  body,  and  are  not 
derived  from  purine.     They  are  primary  products. 

The  Chemical  Nature  of  the  Substances  in  Which  Purine  and 
Pyrimidine  Bases  Exist  in  the  Animal  Body. — In  general  it  may  be  said 
that  the  amino  purines — adenine  and  guanine — together  with  the 
pyrimidine  bases — thymine  and  eytosine — occur  combined  with  phos- 
phoric acid  and  a  carbohydrate  in  the  various  nucleic  acids,  each  of  which 
is  again  combined  with  some  simple  protein  to  form  nuclein,  the  essen- 
tial constituent  of  the  chromatin  of  the  nucleus.  One  of  the  oxypurines, 
hypoxanthine,  may  also  exist  combined  with  phosphoric  acid  and  carbo- 
hydrate to  form  a  substance  present  in  muscle  and  known  as  inosinic 
acid.  The  general  scheme  of  construction  of  a  nucleic  acid  of  animal 
origin  is  illustrated  in  the  following  formula  suggested  by  Levene  and 
Jacobs  :39 


HO 

\ 
\ 

0  =  PO  —  C6HIg04- 

-  CsH4NsO 

/           (hexose) 

(guanine  group) 

/ 
0 

HO 

1 

\ 
\ 

0  =  PO 

i 

1 

—  C6Hs02  — C5H5N,02 

/ 

|  (hexose)      (thymine 

group) 

/ 

HO 

1 
1 
0 

HO 

1 

\ 
\ 

0   =:   PO 

1 

1 

—  CeHs02  —  C4H4N30 

/ 

|  (hexose)      (eytosine 

group) 

/ 

HO 

1 

0 
\ 

Phosphoric  acid 
groups 

1            \     ' 

0  =  PO  —  C6H1004  - 
/           (hexose) 

/ 
HO 

-CSH4X5 
(adenine  group) 

According  to  this  formula  nucleic  acid  may  be  considered  as  a  com- 
pound of  polyphosphoric  acid,  containing  carbohydrate  groups,  which 
serve  to  link  the  phosphoric  acid  molecules  to  those  of  purine  or  pyrimi- 
dine. In  nucleic  acids  of  animal  origin,  such  as  the  example  given 
above,  the  carbohydrate  is  a  hexose,  (i.e.,  contains  6  C-atoms),  whereas 


638  METABOLISM 

in  those  of  plants  (e.  g.,  yeast),  it  is  a  pentose  (5  C-atoms).  It  has  been 
found  necessary  to  introduce  some  terms  to  designate  the  different  parts 
of  the  nucleic  acid  molecule ;  thus,  the  whole  molecule  is  called  a  tetra- 
nucleotide,  each  mononucleotide  molecule  of  which  is  composed  of  a 
phosphoric  acid  molecule  plus  a  nucleoside,  which  again  is  composed  of 
a  purine  or  pyrimidine  nucleus  attached  to  pentose  or  hexose.  The 
nucleoside  is  so  named  because  it  is  similar  in  structure  to  a  glucoside. 
Apart  from  differences  in  the  carbohydrate  group,  it  appears  that 
there  is  a  close  similarity  in  the  structures  of  nucleic  acids  from  dif- 
ferent cells.  This  would  indicate  a  common  function  for  them  all,  which 
may  be  either  of  a  skeletal  or  of  a  physiologic  nature ;  that  is,  nucleic 
acid  may  have  to  do  with  the  sustentacular  material  that  builds  the 
nucleus,  or  it  may  have  to  do  with  .some  physiologic  function  common 
to  all  cells,  such  as  irritability,  or  growth,  or  respiration.  If  nucleic 
acid  is  merely  a  sustentacular  material,  then  the  study  of  the  behavior 
of  chromosomes  and  chromatine  in  cells  can  not  have  the  significance 
that  it  would  have  were  nucleic  acid  concerned  in  the  more  vital  activ- 
ities of  the  nucleus.  All  the  so-called  nuclear  stains  owe  their  specific 
staining  properties  to  the  fact  that  they  are  of  a  basic  nature  and  com- 
bine with  nucleic  acid.  Until  we  know  more  definitely  what  the  exact 
function  of  nucleic  acid  may  be,  it  is  unwise  to  place  too  much  weight 
on  the  behavior  of  the  chromosomes  in  cytologic  researches. 

The  History  of  Nucleic  Acid  in  the  Animal  Body. — AVe  shall  first 
of  all  study  the  manner  in  which  nucleic  acid  may  be  broken  down.  As 
is  to  be  expected  from  its  complex  structure,  various  types  of  enzymes 
are  concerned  in  this  process.  The  first  to  act  are  known  as  the  nucle- 
ases. They  split  the  tetranucleotide  molecule  into  two  dinucleotides, 
which  immediately  afterward  split  further  into  mononucleotides.  Four 
nucleotides,  two  of  purine  and  two  of  pyrimidine,  are  thus  formed  from 
each  molecule  of  nucleic  acid.  Each  nucleotide  molecule  may  now  un- 
dergo decomposition  in  one  of  two  ways:  (1)  either  by  the  splitting  off 
of  phosphoric  acid,  leaving  a  nucleoside  (guanosine  or  adenosine),  or 
(2)  by  the  splitting  off  of  both  phosphoric  acid  and  carbohydrate,  leaving 
free  purine  bases.  Nucleases  have  been  found  which  specifically  effect 
either  of  these  decompositions,  and  they  have  been  called  phospho- 
nucleases*  (1),  and  purine-nucleases  (2),  respectively.  In  the  decompo- 
sition of  nucleic  acid  all  of  the  four  purine  compounds — guanine,  guano- 
sine, adenosine  and  adenine — may  be  formed.  This  is  illustrated  in  the 
accompanying  schema,  in  which  the  nucleic  acid  is  represented  as  a 
purine  nucleotide: 


"The  numbers  refer  to  the  enzymes  indicated  in  the  schema. 


i  RIO    acid    ami   THE   PURINE    BODIES  639 

Nucleic  Acid  (without  the  pyrimidine  group) 


(2)^       (1)  (1)         —"(2) 

/  (Action  of  nucleases)  \ 

e  \l  \  \ 

Guanine  f-(7)  Guanosine  Adenosine  (8)— >  Adenine 

(4)  (5)  (6) 

(Action  of  deaminizing  enzymes) 

Xanthosine  Inosine 

(9)  (Action  of  hydrolyzing  enzymes)  (10) 

Uric  Acidf— (11)  Xanthine  < -(H) ■* Hypoxanthine 

(Action  of  xanthine  oxidase) 

(Jonea.) 

The  next  step  in  the  disintegration  process  is  that  the  amino  group 
is  removed  and  the  corresponding  oxypurine  is  produced.  To  bring  this 
a  1  xuit,  there  exists  a  specific  deaminizing  enzyme  for  each  of  the  above 
amino  compounds,  and  each  enzyme  is  named  according  to  the  exact 
amino  purine  upon  which  it  acts;  thus,  guanase  (3),  guanosine-deaminase 
(4),  adenosine-deaminase  (5),  and  adenase  (6)  have  all  been  identified. 
The  free  base  may  then  be  split  off  from  the  nucleosides  by  specific 
'hydrolyzing  enzymes  (7)  (8)  (9')  (10). 

The  joint  action  of  these  enzymes  leads  to  the  formation  of  oxypurines, 
xanthine  and  hypoxanthine,  which  are  oxidized  to  uric  acid  by  xanthine- 
oxidase  (11). 

In  man  and  the  anthropoid  apes  uric  acid  is  the  end  product  of  the 
above  changes,  but  in  other  mammals  most  of  the  uric  acid  is  further 
oxidized  into  allantoine.  It  has  also  been  found,  except  in  man  and  the 
chimpanzee,  that  extracts  of  organs  such  as  the  liver,  are  capable  of 
decomposing  uric  acid  into  allantoine.  The  identification  of  these  specific 
enzymes  is  sought  by  a  determination  of  the  free  amino-purine  bases 
and  the  phosphoric  acid  produced  by  allowing  an  aqueous  extract  of 
the  tissue  in  question  to  act  on  nucleic  acid  (of  yeast)*  at  body  tempera- 
ture. Another  portion  of  the  digested  mixture  is  then  hydrolyzed  by 
means  of  boiling  sulphuric  acid  and  the  constituents  again  determined. 
From  the  results  it  is  often  possible  to  draw  conclusions  as  to  the  exact 
nature  of  the  enzymes  present. 

The  most  remarkable  outcome  of  this  work  has  been  to  show  that 
the  distribution  of  the  enzymes  is  not  the  same  in  the  tissues  and  organs 
of  different  animals.  Very  briefly,  some  of  the  most  important  results 
that  have  so  far  been  obtained  are  as  follows:  Gastric  and  pancreatic 
juices  do  not  contain  a  trace  of  any  of  the  enzymes.     Intestinal  juice, 

*Yeast  nucleic  acid  is  used  because  it  is  less  resistant'  to  disintegration  than  thymic  nucleic  acid. 


640  METABOLISM 

on  the  other  hand,  contains  a  nuclease  capable  of  splitting  the  poly- 
nucleotides into  mononucleotides.  The  two  pyrimidine  nucleotides  split 
off  do  not  undergo  further  change,  but  the  purine  nucleotides  are  con- 
verted into  nucleosides  (the  enzyme  being  designated  "nucleotidase"). 
Extract  of  the  intestinal  mucosa,  besides  having  the  same  action  as  the 
intestinal  juice,  can  also  decompose  the  purine,  but  not  the  pyrimidine 
nucleosides,  into  carbohydrate  and  purine  groups  (specific  action  of 
"nucleosidase").  A  similar  action  is  produced  by  extracts  of  kidney, 
heart  muscle,  and  liver.  Blood  serum,  hemolyzed  blood,  and  extract  of 
pancreas,  on  the  other  hand,  are  capable  only  of  carrying  the  decompo- 
sition as  far  as  the  mononucleotides. 

Eegarding  the  other  enzymes  mentioned  in  the  above  list,  it  is  im- 
portant to  note  that  they  appear  at  different  stages  in  embryonic  develop- 
ment, and  that  their  distribution  varies  considerably  in  different  species 
of  adult  animal,  the  spleen,  liver,  thymus,  and  pancreas  containing  them 
most  abundantly.  The  distribution  of  enzymes  in  the  organs  of  the 
monkey  resembles  that  in  the  lower  animals  considerably  more  than  it 
does  that  in  man.  Some  remarkable  facts  have  come  to  light  regarding 
guanase  and  adenase,  particularly  that  guanase  is  deficient  in  the  organs 
of  the  pig,  in  the  urine  of  which  animal  it  has  also  been  found  that  the 
purine  bases  are  in  excess  of  the  uric  acid.  This  absence  of  guanase 
no  doubt  accounts  for  the  fact  that  deposits  of  guanine  may  occur  in  the 
muscles,  and  that  these  may  be  so  large  as  to  constitute  the  condition 
known  as  guanine  gout  found  in  this  animal.  Adenase,  on  the  other 
hand,  is  absent  from  the  organs  of  the  rat,  which  again  corresponds  with 
the  fact  that,  when  adenine  is  injected  subcutaneously  into  these  ani- 
mals, it  undergoes  oxidation  without  the  removal  of  its  amino  group. 
In  the  human  organism,  adenase  appears  to  be  absent  from  all  of  the 
organs,  whereas  guanase  is  present  in  the  kidney,  lung  and  liver,  but 
not  in  the  pancreas  or  spleen.    Xanthine-oxidase  exists  only  in  the  liver. 

The  distribution  of  urkase  is  perhaps  the  most  interesting.  It  is  pres- 
ent in  most  of  the  lower  animals.  On  account  of  its  presence  extracts 
of  the  liver,  spleen,  etc.,  in  all  breeds  of  dogs,  with  the  exception  of 
Dalmatians,  rapidly  destroy  uric  acid ;  and  practically  no  uric  acid 
when  injected  subcutaneously  can  be  recovered  unchanged  in  the  urine, 
but  appears  as  allantoine.  Uricase,  however,  is  absent  in  man.  This  has 
been  demonstrated  by  finding  (1)  that  when  uric  acid  is  injected  sub- 
cutaneously, nearly  all  of  it  appears  in  the  urine,  and  (2)  that  uric  acid 
is  not  destroyed  when  extracts  of  the  organs  are  incubated  at  body 
temperature  with  uric  acid  or  its  precursors.  It  must  of  course  be  kept 
in  mind  that,  although  the  uric  acid  is  thus  shown  not  to  be  destroyed 
in  vitro,  it  may  nevertheless  be  destroyed  in  the  living  animal. 


URIC  acid    and   THE    PURINE    BODIES  G41 

The  importance  of  the  above  described  results  rests  in  the  fact  that 
from  them  we  may  hope  to  be  able,  ultimately,  to  stale  exactly  in  a\ l»at 
organs  and  tissues  the  intermediary  metabolic  processes  concerned  in 
nucleic  acid  metabolism  occur.  The  work  at  the  present  time  is  of  spe- 
cial significance,  since  it  represents  one  type  of  evidence  which  we  must 
have  before  we  can  trace  exactly  every  step  in  the  metabolism  of  any 
oilier  biochemical  substance. 

The  absence  of  uricase  from  the  tissues  of  man  places  him  in  a  unique 
position  with  regard  to  the  metabolism  of  nucleic  acid,  and  renders  the 
investigation  of  the  problem  particularly  difficult,  since  animal  experi- 
mentation is  useless.  Recently,  however,  S.  R.  Benedict  has  discovered 
that  the  Dalmatian  breed  of  dog — also  known  as  the  carriage  dog,  and 
having  a  spotted  or  mottled  skin — has  a  purine  metabolism  like  that  of 
man.4  When  fed  on  food  containing  no  purine  substances,  he  excretes 
large  quantities  of  uric  acid,  and  when  the  latter  substance  is  injected 
subcutaneously,  it  is  eliminated  quantitatively  as  such  in  the  urine.  We 
shall  see  later  how  experiments  on  this  animal  have  been  made  use  of 
in  the  investigation  of  problems  of  purine  metabolism  as  applied  to  man. 
In  all  other  animals  most  of  the  uric  acid  is  oxidized  to  allantoine  before 
being  excreted.  The  degree  to  which  this  occurs  varies  between  79 
and  98  per  cent  of  the  uric  acid  in  different  species.  This  has  been 
called  the  uricolytic  index  (Hunter  and  Givens). 

The  Balance  between  Intake  and  Output  of  Purine  Substances  under 
Various  Physiologic  and  Pathologic  Conditions. — The  main  purine  ex- 
cretory product  in  man  is  uric  acid,  but  there  is  also  a  certain  amount 
of  purine  bases.  The  presence  of  uric  acid  has  attracted  attention  for 
a  great  many  decades  in  medical  investigation,  because  of  the  relative 
ease  with  which  it  can  approximately  be  determined  quantitatively,  and 
because  of  the  well-known  fact  that  it  may  be  responsible  for  certain 
diseases,  such  as  gout,  when  it  accumulates  in  the  tissues  in  an  insoluble 
form.  On  a  diet  containing  meat,  or  more  particularly  on  one  con- 
taining glandular  substances,  the  total  daily  excretion  of  uric  acid  is 
very  considerably  greater  than  when  the  diet  contains  no  such  food 
stuffs.  The  conclusion  which  Burian  and  Schur43  drew  from  this  ob- 
servation is  that  purine  must  be  partly  of  exogenous  and  partly  of 
endogenous  origin.  In  other  words,  some  of  it  is  derived  more  or  less 
directly  from  performed  purine  substances  in  the  food,  and  the  remain- 
der from  the  purine  constituents  of  the  animal's  own  tissues. 

Endogenous  Purines. — It  was  thought  that  a  definite  proportion  of 
each  of  the  administered  purines  could  be  invariably  recovered  from 
the  urine.  Although  this  has  not  been  found  to  be  exactly  true,  there 
is  nevertheless  a  certain  constancy  in  the  proportion  of  administered 


(J42  METABOLISM 

purine  that  is  excreted.  Thus,  Mendel  and  Lyman  have  found  recently 
that  about  60  per  cent  of  injected  hypoxanthine,  50  per  cent  of  xan- 
thine, 19-30  per  cent  of  guanosine,  and  30-37  per  cent  of  adenine  were 
eliminated  as  uric  acid.  When  combined  purines — i.  e.,  nuclear  mate- 
rial— are  given,  only  a  small  proportion  of  the  purine  reappears  as  uric 
acid  in  the  urine.  There  is,  therefore,  a  general  parallelism  between 
the  purine  content  of  the  food  and  that  of  the  urine,  which  indicates  that 
purine-rich  food  should  be  eliminated  from  the  diet  of  patients  who  are 
suffering  from  deposition  of  insoluble  urate  in  the  tissues,  as  in  gout. 
The  fate  of  the  purine  that  disappears  in  the  body  is  unknown ;  some  of 
it  may  be  decomposed  in  the  intestine,  but  why  so  much  of  the  remainder, 
after  absorption  by  the  blood,  should  disappear  is  a  mystery,  since  no 
uricase  can  be  discovered  in  any  of  the  organs  or  tissues.  The  destroyed 
purines  can  not  be  shown  to  influence  any  of  the  other  well-known 
nitrogenous  metabolites  of  the  urine. 

The  following  table  of  experiments  by  Taylor  and  Rose45  may  serve 
to  illustrate  these  points.  The  subject  was  placed  on  a  purine-free  diet 
consisting  of  milk,  eggs,  starch  and  sugar,  for  three  days.  After  this 
period  a  part  of  the  total  nitrogen  (3  grams)  was  supplied  as  sweet- 
breads— thymus  gland,  etc. — containing  a  high  percentage  (0.482)  of 
purine  nitrogen;  for  another  period  of  four  days  still  more  of  the  nitro- 
gen (6  grams)  was  replaced  by  sweetbread  nitrogen;  and  this  was  fol- 
lowed by  a  final  period  in  which  the  original  diet  of  milk,  etc.,  without 
purine  substances,  was  restored.     The  following  table  gives  the  results: 


1st  pei;ioi> 

4th  period 

PURINE-FREE 

2nd  period 

3rd  period 

PURINE-FREE 

DIET 

DIET 

Total  urinary  N 

8.9 

8.7 

9.1 

8.8 

Urea  N  and  NH2 

7.3 

7.1 

7.1 

7.05 

Creatinine 

0.58 

0.55 

0.56 

0.47 

Purine  N  (total) 

0.11 

0.17 

0.26 

0.10 

Uric  acid  N 

0.09 

0.14 

0.24 

0.07 

Remainder  N 

0.91 

0.88 

1.18 

1.18 

The  increase  of  uric  acid  accounted  for  less  than  half  of  the  purine 
nitrogen  ingested.  This  appeared  as  uric  acid,  the  excretion  of  purine 
bases  being  practically  unchanged. 


CHAPTER  LXXm 

URIC  ACID  AND  THE  PURINE  BODIES   (Cont'd) 

SOURCE  OF  ENDOGENOUS  PURINES 

Even  after  the  entire  elimination  of  all  purine  substances  from  the 
food  in  the  ease  of  man,  purine  continues  to  be  excreted  in  the  urine 
as  uric  acid.  This,  as  above  remarked,  is  called  endogenous  excretion. 
At  first  it  was  thought  by  Burian  and  Schur  that  the  total  nitrogen  of 
the  purine-free  diet  could  be  considerably  varied  -without  causing  any 
alteration  in  the  amount  of  the  endogenous  purine  excretion,  but  a  rep- 
etition of  the  work  has  shown  that,  when  these  changes  are  of  consider- 
able magnitude,  the  endogenous  moiety  does  not  remain  constant.  This 
has  already  been  demonstrated  in  the  table  on  Folin's  results  (see  page 
614),  and  is  still  better  illustrated  in  the  accompanying  table,  which 
shows  the  excretion  of  uric  acid  and  coincidently  of  urea  from  hour  to 
hour  in  the  urine  after  taking  food  which  is  free  from  nuclein  or  purine 
substances.  After  a  fast  of  six  hours,  a  diet  consisting  of  bread  and 
potatoes  was  taken  at  1:30,  and  the  urea  and  uric  acid  measured  in  the 
urine  each  hour  thereafter.* 


TIME 

UREA 

URIC  ACID 

AMOUNT  OF  URINE 

GM. 

MG. 

c.c. 

10-11 

1.07 

26 

175 

11-12 

1.13 

27 

118 

12-1    P.M. 

1.07 

24 

164 

1-2  (meal) 

0.64 

21 

60 

2-3 

1.12 

22 

43 

3-4 

1.16 

38 

41 

. 

4-5 

0.S4 

40 

53 

5-6 

1.16 

56 

59 

6-7 

1.20 

39 

56 

7-8 

1.37 

30 

95 

8-9 

1.47 

33 

183 

9-10 

1.33 

24 

155 

10-11 

1  33 

23 

180 

(Hopkins  and  Hope.)46 

A  postprandial  increase  of  endogenous  purine  excretion  is  very  dis- 
tinct, and  it  indicates  that  during  the  process  of  assimilation  something 
must  he  occurring  in  the  organism  which  entails  the  production  of  purine 

♦These  investigations  should-  be  repeated,  since  there  is  some  question  as  to  whether  the  method 
of  analysis    employed    (Folin-Shaffer)    is   suitable   for   determining    hourly    uric-acid   excretion. 

643 


644  METABOLISM 

from  the  organism  itself.  As  to  what  this  may  he,  it  is  impossible  to 
say.  It  may  be  associated  with  the  work  of  the  gastric  and  intestinal 
glands,  which  recalls  the  interesting  suggestion,  originally  made  by 
Horbaczewski,  that  ingested  substances  increase  the  excretion  of  uric 
acid  by  causing  a  leucocytosis,  the  purine  being  derived  from  the  nucleic 
acid  set  free  when  the  leucocytes  become  broken  down.  That  this  is 
not  the  correct  explanation,  however,  is  indicated  by  the  fact  that  in- 
gested substances  that  give  rise  to  an  increased  number  of  leucocytes 
affect  the  excretion  of  uric  acid  during  the  period  the  leucocytes  are 
present  in  the  blood,  and  not  after  they  have  disappeared,  which  would 
have  to  be  the  case  were  the  uric  acid  a  product  of  purine  substances 
liberated  by  their  breakdown.  This  would  indicate  that  the  purine  sub- 
stance is  a  metabolic  product  of  the  living  leucocytes  and  not  a  break- 
down product  of  those  that  are  dead.  It  should  be  noted  that  the  increase 
in  the  postprandial  uric-acid  excretion  occurs  earlier  than  that  of  urea. 

The  most  pressing  question  concerns  the  origin  of  the  endogenous 
purines.  Uric  acid  is  the  purine  with  which  we  are  most  concerned  in 
the  case  of  man,  and  chemistry  shows  us  that  it  may  be  produced  either 
by  the  oxidation  of  the  lower  purines — namely,  of  those  which  are  the 
constituent  parts  of  the  nucleic-acid  molecule — or  by  a  synthesis  of  two 
urea  molecules  with  a  carbon  residue  containing  three  carbon  atoms. 
There  are  consequently  two  sources  from  which  the  endogenous  purine 
excretion  in  man  may  be  derived  :  (1)  synthesis  of  two  urea  molecules, 
and  (2)  oxidation  of  the  lower  purines. 

We  will  consider  first  the  possibility  of  synthesis.  In  birds  and 
reptiles  practically  all  the  nitrogen  is  excreted  in  the  form  of  uric  acid, 
and  it  is  easy  to  show  that  this  has  been  produced  in  the  organism  by 
the  synthesis  of  urea  with  carbon-rich  residues,  occurring  mainly  in  the 
liver.  Minkowski  found  that  by  removing  the  liver  from  geese,  which 
is  a  comparatively  simple  operation  on  account  of  an  anastomotic  vein 
between  the  portal  and  the  renal  veins,  the  uric  acid  in  the  urine  became 
very  markedly  decreased  and  ammonium  lactate  took  its  place  (page 
618).  Since  we  know  that  ammonium  in  the  animal  body  is  ordinarily 
converted  into  urea,  we  may  conclude  from  this  observation  that  some- 
thing has  occurred  to  prevent  the  synthesis  of  urea  into  uric  acid.  In 
confirmation  of  this  conclusion  it  was  subsequently  found  that,  if  am- 
monium lactate  was  added  to  the  blood  perfused  through  the  isolated 
liver  of  the  goose,  uric  acid  was  produced  in  the  perfusion  fluid.*  Fur- 
thermore, when  birds  and  reptiles  are  fed  wTith  ammonium  salts  or 
with  the  degradation  products  of  protein,  there  is  an  increase  in  the  ex- 


*The  reason  for  the  formation  of  this  relatively  insoluble  metabolite  in  place  of  the  soluble  urea 
is  connected  in  some  way  with  the  fact  that  birds  and  reptiles  do  not  take  such  large  quantities 
of  water  with  their  food  as  other  animals. 


i  MO    ACID   AND   THE   PURINE   BODIES  645 

cretion  of  uric  acid  instead  of  area.     Everything  which  in  a   mammal 

tends  to  cause  an  increase  in  urea  excretion  causes  in  birds  and  reptiles 
a  similar  increase  in  the  excretion  of  uric  acid. 

In  the  early  days  of  research  in  the  uric-acid  problem,  not  inconsid- 
erable mistakes  were  made  on  account  of  failure  to  recognize  the  essen- 
tial difference  in  the  metabolism  of  uric  acid  in  birds  and  mammals, 
and  the  tendency  for  some  time  after  the  exact  state  of  affairs  was 
discovered  was  to  consider  that  in  mammals  none  of  this  synthetic  proc- 
ess occurs.  The  latter  view,  however,  is  surely  incorrect,  for  a  cer- 
tain amount  not  only  of  uric  acid  itself  but  of  the  lower  purine  bodies 
can  be  produced  by  synthesis  in  the  mammalian  body.  Thus,  Ascoli  and 
Izar47  discovered  that  uric  acid  could  be  made  either  to  disappear  or 
to  be  formed  when  a  minced  preparation  of  liver  was  incubated,  depend- 
ing upon  whether  oxygen  or  carbon  dioxide  was  bubbled  through  it. 
With  oxygen  uric  acid  disappeared,  whereas  with  carbon  dioxide  uric 
acid  accumulated,  indicating  that  in  the  presence  of  this  gas  the  destroyed 
uric  acid  became  reformed  from  the  disintegration  products  of  the  oxy- 
genation process.  As  similar  results  were  obtained  from  the  livers  of 
birds,  it  is  clear  that  no  essential  difference  exists  between  the  purine 
metabolic  processes  occurring  in  the  livers  of  birds  and  of  mammals. 
The  difference  is  a  quantitative  not  a  qualitative  one. 

Regarding  the  chemical  nature  of  the  product  into  which  uric  acid  is 
broken  down  and  from  which  it  may  be  resynthesized,  it  has  been  pos- 
sible so  far  to  identify  but  one  substance — namely,  dialuric  acid.  This 
is  a  perplexing  result,  for  from  all  other  investigations  it  would  appear 
that  in  mammals,  with  the  exception  of  man  and  the  anthropoid  apes, 
uriease  splits  uric  acid  into  allantoine  (see  page  640),  which  substance, 
however,  when  added  to  liver  extract  did  not  cause  any  uric  acid  to  be 
formed ;  nor  did  any  of  the  other  known  decomposition  products  of  uric 
acid  have  such  a  result.  The  chemical  reaction  involved  in  the  produc- 
tion of  uric  acid  from  dialuric  acid  and  urea  is  indicated  as  follows: 

NH  —  C  =  O 
/ 
/ 
/ 
o  =  c  c:  =  h.oh  II   ;NH 


\ 
\ 
\ 


\ 

c  =  o 

/ 


nh  —  c ;  =  o  n  ;  xii 

(dialuric  acid)  (urea) 

The  synthesis  of  uric  acid  is  brought  about  by  the  combined  action 
of  a  thermolabile  enzyme  in  the  blood  and  a  thermostable  body  in  the 
tissues.    An  aqueous  extract  of  blood-free  liver  of  the  dog  can  destroy 


646  METABOLISM 

uric  acid  only  in  the  presence  of  oxygen ;  it  can  not  reform  it  even  in 
the  presence  of  carbon  dioxide.  On  the  other  hand,  blood  serum  can 
not  reform  uric  acid,  whereas  a  mixture  of  the  bloodless  liver  extract 
and  blood  serum  produces  uric  acid  readily  under  suitable  conditions. 
Boiling  of  the  liver  extract  does  not  affect  the  result,  but  boiling  of  the 
blood  serum  renders  it  incapable  of  exerting  its  joint  action  with  the 
bloodless  liver  extract. 

These  experiments  with  dog's  liver  serve  only  as  circumstantial  evi- 
dence that  uric-acid  synthesis  occurs  in  mammals  as  well  as  in  birds. 
More  direct  proof  that  purine  synthesis  occurs  in  mammals  is  as  follows: 
(1)  It  Mas  discovered  long  ago  by  Miescher  that  salmon,  after  leaving 
the  sea  to  ascend  the  rivers,  have  a  well-developed  muscular  system,  but 
that  in  the  upper  reaches  of  the  stream  the  muscular  system  becomes 
considerably  atrophied  and  the  testes  enormously  developed.  As  the 
fish  takes  no  food  during  the  migration,  there  must  be  conversion  of 
the  protein  of  the  muscles  into  the  cellular  tissue  of  the  sexual  glands, 
and  nucleic  acid  must  be  produced.  (2)  A  hen's  e^  before  its  incuba- 
tion contains  practically  no  nucleic  acid,  whereas  after  development  has 
well  started  nucleic  acid  increases  by  leaps  and  bounds.  Similarly  the 
eggs  of  insects  increase  in  purine  content  very  markedly  as  development 
proceeds.  (3)  Milk  contains  practically  no  purine  derivative,  and  yet 
when  it  is  fed  to  young  growing  animals,  the  organs  lay  on  purine  sub- 
stances abundantly.  In  general,  indeed,  it  may  be  said  that  the  combined 
purine  increase  is  in  proportion  to  the  increase  in  body  weight  on  the 
milk  diet.  (4)  In  Osborne  and  Mendel's  experiments  already  alluded 
to,  it  has  been  shown  that  adequate  growth  depends  primarily  on  the 
nature  of  the  protein  building  stones,  and  not  upon  the  purine  content 
of  the  food.  (5)  An  objection  might  be  raised  to  these  results  on  the 
score  that  they  do  not  apply  to  the  adult  mammal.  Investigation  of 
the  problem  has  hitherto  been  seriously  impeded  by  the  fact  that  no  or- 
dinary laboratory  animals  were  known  in  which  uric  acid  is  excreted  in 
the  urine.  The  discovery  that  this  occurs  in  the  Dalmatian  dog  has, 
however,  made  it  possible  for  S.  R.  Benedict41  to  show,  not  onlv  that 
after  increasing  the  amount  of  nonpurine  food  there  was  a  very  distinct 
increase  in  the  uric-acid  excretion,  but  also  that  when  the  animal  was 
kept  for  a  year  on  such  foods  there  was  excreted  a  total  amount  of  uric 
acid  at  least  ten  times  greater  than  could  have  come  from  the  traces 
unavoidably  included  in  the  food. 

Regarding  the  chemical  nature  of  the  substance  from  which  the  purine 
is  synthesized,  we  know  at  present  practically  nothing.  No  doubt  some 
of  the  protein  building  stones  functionate  in  this  capacity,  pyrimidine 
being  probably  the  product  that  is  first  formed.     Thus,  pyrimidine  may 


URIC    A.CID    AN'D   THE    PURINE    BODIES  647 

be  produced  ;is  a  result  of  t lie  combination  of  amino  malonic  acid  will) 
urea,  the  amino-malonic  acid  being  produced  by  condensation  of  hydro- 
cyanic-acid molecules: 

3  HCN-*H,N-CH(CN),  +  CO(NB:),--»NH-CO 

I        ! 
co   cnh, 

I      II 

NH  -  CNH2 
(hydrocyanic      (amino-malonic      (urea)     (oxy-diamino-pyrimidine) 

acid)  nitrile) 

Another  possible  source  of  pyrimidine  is  the  oxidation  of  arginine  to 
guanidine-propionic  acid,  which  then  condenses  to  form  amino  pyrimi- 
dine. 

Purine  synthesis  undoubtedly  occurs  in  the  mammalian  body,  but  it 
is  difficult  to  recognize  in  metabolism  investigations  because  it  is  a  slow, 
continuous  process.  The  probability  of  its  occurrence,  however,  is  indi- 
cated by  such  results  as  those  described  on  page  614,  in  which  increase 
in  purine  excretion  is  observed  after  varying  the  intake  of  food,  even 
when  this  is  itself  entirely  free  from  purine  substances.  Whether  or  not 
changes  in  the  activity  of  purine  synthesis  occur  in  conditions  of  disease 
is  a  question  which  awaits  investigation. 

The  Influence  of  Various  Physiologic  Conditions,  of  Drugs,  and  of 
Disease  on  the  Endogenous  Uric-acid  Excretion. — Muscular  exercise  was 
thought  by  Burian  to  cause  an  increased  excretion  of  uric  acid,  from 
which  he  drew  the  conclusion  that  the  hypoxanthine  present  in  compara- 
tively large  amount  in  muscular  extract,  or  its  precursor,  inosinic  acid, 
must  be  an  important  source  of  endogenous  uric  acid.  Other  observers 
(Leathes,  etc.)  have  found  that  strenuous  exercise  causes  a  distinct  in- 
crease in  urie-acid  excretion,  which,  however,  is  much  less  marked  on 
repetition  of  the  same  kind  of  exercise  on  the  next  day.  If  some  new 
kind  of  muscular  work  is  performed,  another  increase  in  uric  acid  will 
result.  There  are  still  other  investigators  who  deny  that  muscular  work 
has  any  influence  on  uric-acid  excretion. 

It  has  been  observed  by  several  investigators  that  the  endogenous 
purine  excretion  is  distinctly  higher  during  the  waking  hours  than  during 
sleep.  This  can  not  be  shown  to  depend  on  variations  in  the  urinary 
function,  and  since  it  is  decidedly  doubtful  whether  ordinary  muscular 
activity  has  any  influence,  the  diurnal  variation  is  most  difficult  to 
account  for.  The  endogenous  excretion  in  man  is  not  the  same  for 
different  individuals,  even  when  calculated  for  the  same  body  weight;  it 
varies  between  0.12  and  0.20  per  cent  purine  nitrogen  in  an  adult  man. 
It  remains  remarkably  constant  for  a  given  individual  from  time  to 
time,  being  unaffected  by  moderate  degrees  of  variation  in  the  amount 


648  METABOLI-.M 

of  food  taken  provided  this  he  purine-free;  when,  however,  the  amounts 
are  extremely  variable,  changes  are  produced  (see  page  614). 

In  disease,  fever  causes  an  increased  excretion.  This  has  been  most 
clearly  shown  by  Leathes,  who  took  a  large  enough  dose  of  antityphoid 
serum  to  produce  a  distinct  degree  of  fever  (103°  F.),  and  found  that 
an  increase  in  uric-acid  excretion  occurred.  That  increased  combustion 
processes  occurring  in  the  tissues  were  responsible  for  the  uric  acid, 
was  shown  by  the  same  author,  who  caused  a  similar  increase  by  sub- 
jecting himself  to  cold  baths  for  a  considerable  period  of  time.  The  in- 
creased loss  of  heat  thus  induced  stimulated  the  combustion  processes  in 
the  body  so  as  to  maintain  the  body  temperature,  and  as  a  result  there 
was  an  increase  in  uric-acid  excretion.  It  has  long  been  known  that  an 
excessive  amount  of  uric  acid  is  excreted  in.' leucocythemia.  The  nuclein 
of  disintegrated  leucocytes  is  commonly  held  responsible  for  the  increase. 
Naturally,  much  work  has  been  done  on  the  endogenous  and  exogenous 
purine  excretion  in  gout.  Xo  very  striking  anomalies  of  excretion  have, 
however,  been  brought  to  light,  except  perhaps  that  after  the  ingestion 
of  purine-rich  foodstuffs  it  takes  longer  for  the  resulting  exogenous  ex- 
cretion to  develop  and  pass  away. 

Certain  drugs  affect  the  excretion  of  uric  acid.  Salicylic  acid  is  said 
to  cause  an  increased  excretion,  and  citrates  certainly  have  this  effect. 
In  both  eases  the  increase  is  followed  by  a  compensatory  fall,  which 
indicates  that  these  drugs  act  by  facilitating  the  excretion  rather  than 
by  influencing  the  metabolic  processes  that  are  the  source  of  the  uric 
acid.  The  effect  of  caffeine  has  been  very  carefully  investigated.  Given 
to  the  Dalmatian  dog,  referred  to  above.  S.  R.  Benedict  found  that  a 
small  dose  caused  a  slight  decrease,  but  that  a  larger  dose  had  practically 
no  effect,  although  there  was  a  notable  retention  of  nitrogen.  On  man. 
however,  different  results  were  secured,  for  it  was  found  that  when  1 
gram  of  caffeine  was  given  daily  for  several  days,  a  slight  but  definite 
progressive  increase  in  the  endogenous  uric-acid  excretion  occurred,  and 
it  lasted  for  10  days  after  the  caffeine  administration  was  discontinued. 
Liberal  allowance  of  this  alkaloid  may,  therefore,  not  be  quite  so  innocu- 
ous as  it  is  assumed  to  be. 

Uric  Acid  of  Blood. — In  all  of  the  investigations  considered  above, 
the  behavior  of  uric  acid  is  judged  from  the  amount  of  it  excreted  in 
the  urine.  Valuable  though  such  results  must  be,  their  interpretation  is 
always  difficult,  since  two  factors  that  are  quite  independent  of  each 
other  have  to  be  kept  in  mind — namely,  the  production  of  the  uric  acid 
in  the  orsrans  and  tissues  and  its  excretion  by  the  kidneys.  In  connection 
with  the  latter  factor,  we  must  also  consider  the  method  of  transporta- 
tion of  uric  acid  by  the  blood  from  its  place  of  production  (or  absorp- 


URIC   ACID   AND   THE   PURINE   BODIES  649 

tion)  to  tlif  kidneys.  These  problems  have  recently  been  very  consider- 
ably simplified  by  the  elaboration  of  an  accurate  method  for  the  estima- 
tion of  the  uric-acid  content  of  blood. 

By  observing  changes  in  the  amount  of  uric  acid  in  the  blood  rather 
than  in  the  urine,  the  excretory  factor  is  partly  controlled,  and  it  can 
be  completely  so  if  urine  and  blood  arc  both  investigated.  Thanks  to 
the  work  of  Folin,  it  is  now  possible  to  determine  with  an  extreme  de- 
gree of  accuracy  the  uric  acid  in  as  little  as  10  c.c.  of  blood.  The  impor- 
tance of  this  achievement  will  be  appreciated  when  we  state  that  prior 
to  Folin 's  work  no  method  existed  by  which  uric  acid  could  be  approx- 
imately measured  even  when  large  quantities  of  blood  were  available. 

Much  of  the  work  that  has  been  done  by  the  use  of  this  new  method 
has  so  far  applied  to  the  amount  of  uric  acid  in  the  blood  of  man  in 
various  diseases.  We  shall  refer  to  these  results  immediately,  but 
meanwhile  it  is  important  to  call  attention  to  some  very  suggestive 
observations  concerning  the  condition  of  uric  acid  in  the  blood.  For 
many  years  there  have  been  investigators  who  have  thought  that  uric 
acid  can  not  be  simply  dissolved  in  the  blood  plasma,  like  sugar  or  some 
inorganic  salt.  It  is  believed  by  many  that  at  least  a  portion  of  the  uric 
acid  circulates  in  combination  with  nucleic  (thymic)  acid  (see  page  637), 
which  would  account  for  the  fact  that  some  purines  are  catabolized  in 
the  body  when  they  are  given  in  a  combined  state,  as  thymic  acid,  but 
are  excreted  unchanged  when  ingested  in  a  free  state.  When  given  freely, 
certain  purines — adenine,  for  example — may  moreover  cause  inflamma- 
tion and  calculus  formation  in  the  kidneys  of  dogs,  a  result  not  obtained 
when  thymic  acid  is  fed. 

Other  observers  have  concluded  that  uric  acid  exists  as  two  isomeric 
varieties,  lactam  and  lactim,  the  monosodium  salts  of  which  are  of  un- 
equal stability.  The  less  stable  a-salt  is  much  more  soluble  in  blood 
serum  than  the  stable  /?-salt.  It  is  the  a-salt  that  becomes  increased  in 
the  blood  in  gout,  the  deposition  of  urates  in  the  tissues,  which  is  the 
most  characteristic  symptom  of  this  disease,  being  caused  by  conversion 
of  the  a-salts  into  /?-salts.  The  structural  formulas  of  the  two  isomers 
are  as  follows: 

H.N-C  :  O  N-C.OH 

II  II     II 

O  :  C     C-MI  HO.C     C  -  Nil 

I      II  \  I       I  \ 

CO  C.OH 

I      II  /  11/ 

H.N  -  C  -  NH  N  =  C  -  N 

[lactam  modification  forming  [lactim  modification  foimiug 

unstable  a-urates]  stable  ^-urates] 

(relatively  soluble)  (relatively  insoluble) 


650  METABOLISM 

The  most  recent  Avork  of  S.  R.  Benedict  has  shoAvn  that  uric  acid  ex- 
ists, chiefly  in  combination  in  the  blood  of  most  mammals  but  not  in 
that  of  the  bird.  It  AA-as  found,  for  example,  that  fresh  ox-blood  exam- 
ined by  the  Folin  method  contains  only  0.0005  gm.  free  uric  acid  per  100 
gm.  of  blood;  after  boiling  the  protein-free  blood  filtrate  Avith  hydro- 
chloric acid,  hoA\-eA'er,  the  uric  acid  increased  by  about  ten  times.  This 
larger  amount  was  also  found  present  in  Avhole  blood  that  had  been 
alloAA-ed  to  stand  for  some  time,  indicating  that  the  uric-acid  compound 
can  be  split  by  means  of  an  enzyme.  The  compound  exists  in  the  cor- 
puscles and  not  in  the  plasma.  It  is  of  some  significance  that  after  thus 
setting  free  the  uric  acid,  there  should  be  about  50  per  cent  more  of  it 
present  in  the  blood  of  the  ox  than  in  that  of  the  bird,  AA'here  most  exists 
in  a  free  state  in  the  serum,  although  the  urine  of  the  ox  contains  only 
the  smallest  trace  of  uric  acid,  and  that  of  the  bird  is  loaded  A\-ith  it. 
Iinestigation  of  the  condition  of  uric  acid  in  human  blood  is  at  present 
in  progress. 

Uricemia  in  Gout  and  Nephritis 

The  practical  application  of  these  observations  is  particularly  impor- 
tant in  connection  AA'ith  the  etiology  of  gout.  In  typical  cases  of  this  dis- 
ease, the  uric  acid  of  the  blood  increases  from  its  normal  A^alue  of  1  to 
3  mg.  per  cent  to  nearly  10  mg.,  indicating  a  considerable  degree  of 
renal  insufficiency.  This  uricemia  can  not  in  itself,  hoAveA-er,  be  the  cause 
of  the  deposition  of  urates  in  the  joints,  because  it  also  occurs  in  other 
diseases  Avith  renal  retention,  such  as  nephritis.  Moreover,  the  blood 
serum  is  capable  of  dissolving  much  larger  quantities  of  uric  acid  than 
are  eArer  found  present  in  it  in  gout.  The  real  cause  for  the  gouty  deposits 
must  depend  on  some  change  affecting  the  blood  so  as  to  alter  the  form 
in  AAThich  uric  acid  exists  therein,  Avith  the  result  that  it  is  excreted  into 
the  joints  and  deposited  there. 

Other  diseases  showing  uricemia  are  lead  poisoning  and  nephritis.  In 
the  latter  disease  the  damaged  excretory  function  of  the  kidney  is 
manifested  first  of  all  by  an  increase  in  the  uric-acid  content  of  the 
blood,  accompanied  later  by  a  retention  of  urea  and  later  still  by  one 
of  creatinine.  The  severity  of  the  renal  iirvolvement  may  therefore  be 
ganged  by  determining  the  percentage  of  these  three  metabolites.  On 
account  of  the  importance  of  these  facts  from  a  clinical  standpoint,  AA-e 
append  a  table  containing  results  secured  by  Myers  and  Fine,  in  AA'hich 
the  behavior  of  the  metabolites  in  the  blood  is  shown  in  relationship 
to  the  severity  of  the  case  as  gauged  by  the  blood  pressure. 


IKIC    ACID   AND    Till:    IMKINE   BODIES 


651 


Uric  Acid,  Urea  X  and  Creatinine  of  Blood  in  Gout  and  Early  and  Late  Nephritis 


OHIO 

ACID 

UREA  N 

CREATININE 

SYSTOLIC 

DIAG  .v  'si  s 

MG.  TO    100   C. 

C. 

BLOOD 

BLOOD 

PRESSURE 

Typical  Cases  of  Gout 

9.5 

13 

1.1 

230 

8.4 

12 

2.2 

164 

7.2 

17 

2.4 

200 

6.8 

14 

1.7 

Typical  Early  Interstitial  Nephritis 

9.5 

25 

2.5 

185 

8.0 

37 

2.7 

150 

5.0 

37 

3.9 

130 

7.1 

16 

2.0 

6.6 

24 

•      3.3 

185 

6.3 

18 

2.1 

8.7 

20 

3.6 

100 

7.0 

33 

2.6 

117 

6.3 

31 

2.1 

6.3 

23 

2.4 

150 

Chronic    Diffuse    and    Chronic    Inter- 

8.0 

80 

4.8 

240 

stitial  Nephritis 

4.9 

17 

2.9 

170 

8.3 

72 

3.2 

238 

5.3 

21 

1.9 

145 

9.5 

44 

3.5 

210 

2.5 

19 

1.9 

120 

7.7 

67 

3.1 

6.7 

17 

1.6 

165 

8.3 

39 

2.9 

6.5 

24 

3.0 

200 

Typical  Fatal  Chronic  Interstitial 

22.4 

236 

16.7 

210 

Nephritis 

15.0 

240 

20.5 

225 

14.3 

263 

22.2 

220 

13.0 

90 

11.1 

265 

8.7 

144 

11.0 

225 

(Myers   and    Fine:      Arch.   Int.    Med.,   1916.) 

Lastly,  regarding  the  influence  of  drugs  on  the  blood  uric  acid  in  dis- 
ease, it  has  been  found  by  Fine  that  both  atophan  and  salicylates  cause 
a  pronounced  decrease  in  the  amount,  but  that  it  gradually  rises  to  the 
old  level  even  while  administration  of  the  drugs  is  being  continued. 

Important  contributions  to  the  behavior  of  uric  acid  in  blood  are 
constantly  appearing  at  present,  mainly  from  the  laboratories  of  Folin 
in  Boston,  of  S.  R.  Benedict,  and  of  Myers  and  Fine  in  New  York. 


CHAPTER  LXXIV 

THE  METABOLISM  OF  THE  CARBOHYDRATES 

The  healthy  animal  organism  is  capable  of  rapidly  oxidizing  large 
quantities  of  carbohydrate,  as  is  evident  from  the  following  facts:  If 
carbohydrate  is  given  to  a  starving  animal,  (1)  the  energy  output  very 
shortly  afterward  increases;  (2)  the  respiratory  quotient  also  increases, 
indicating  that,  relatively  to  oxygen  intake,  more  carbon  dioxide  is  being 
excreted  (see  page  647)  ;  and  (3)  none  of  the  ingested  carbohydrate 
makes  its  appearance  in  the  excreta.  Indeed,  of  the  three  proximate 
principles  of  food,  carbohydrate  is  the  most  available  for  combustion 
in  the  animal  body.  It  may  therefore  be  considered  as  the  quickly 
available  fuel  for  the  body  furnaces. 

CAPACITY   OF   THE  BODY  TO   ASSIMILATE   CARBOHYDRATES 

Assimilation  Limits. — When  the  limit  to  the  amount  of  carbohydrate 
that  the  organism  can  metabolize  is  overstepped,  some  of  it  appears  in 
the  urine.  The  amount  that  can  be  tolerated  without  causing  glycosuria 
is  commonly  called  the  assimilation  or  saturation  limit.  The  use  of  the 
term  "limit"  is,  however,  very  unfortunate,  for  it  implies  that  beyond 
this  point  the  organism  is  capable  of  dealing  with  no  more  carbohy- 
drate, which  is  far  from  being  the  case,  for  if  a  larger  amount  is  taken, 
only  a  small  trace  of  the  excess  will  appear  in  the  urine.  When  the 
urine  is  allowed  to  collect  for  twenty-four  hours,  the  mixed  specimen 
shows  no  trace  of  glucose  in  the  majority  of  healthy  individuals  after 
the  ingestion  of  200  gm. ;  after  300  gm.  a  somewhat  higher  percentage 
of  cases  develop  a  mild  glycosuria,  but  frequently  none  is  evident  even 
after  500  gm.  Beyond  the  last  mentioned  amounts  the  limit  of  ingestion 
is  reached,  on  account  of  nausea,  etc.,  and  it  is  improbable  that,  even 
if  larger  amounts  could  be  tolerated,  any  more  of  the  dextrose  would 
be  absorbed  than  with  300  or  400  gm.  The  testing  of  the  so-called 
assimilation  limit  has  been  considered  an  important  aid  in  tlie  diagnosis 
of  early  cases  of  diabetes,  the  characteristic  feature  of  such  cases  being 
the  inability  of  the  organism  to  assimilate  properly  the  usual  quantity 
of  carbohydrate  contained  in  the  diet. 

It  has  been  found  that  to  make  the  results  of  any  value,  certain 
conditions  must  be  fulfilled  in  applying  the  assimilation  test.    The  most 

652 


THE    METABOLISM   OF   THE   CARBOHYDRATES  653 

important  of  these  concerns  the  activities  of  the  gastrointestinal  appa- 
ratus ;it  the  time  the  sugar  is  given,  Eor  ii  has  been  found  that  if  other 
foodstuffs  are  being  absorbed  at  the  same  time  as  the  sugar,  more  of 
the  latter  can  be  tolerated  than  -when  the  sugar  alone  is  being  absorbed. 
It  has  therefore  been  customary  to  give  the  sugar  dissolved  in  water, 
or  in  weak  eoffee,  the  first  tiling  in  the  morning  after  the  patient  awakes; 
i.  e.,  at  least  twelve  to  sixteen  hours  after  the  last  meal  was  taken.  In 
making  these  tests  the  urine  voided  before  the  sugar  is  estimated  should 
of  course  itself  be  thoroughly  examined  for  reducing  substances,  and 
the  urine  should  be  collected  every  ninety  minutes  and  examined  by  a 
reliable  test  (Benedict's  or  Nylander's).* 

Although  a  limit  is  set  to  the  ability  of  the  organism  for  retaining 
sugar  (mono-  or  di-saccharides),  this  does  not  seem  to  apply,  in  healthy 
individuals  at  least,  when  starches  (polysaccharides)  are  ingested.  Thus, 
it  is  a  well-known  fact  that  people  can  eat  enormous  quantities  of  pota- 
toes or  of  bread  without  the  appearance  of  any  trace  of  reducing  sub- 
stances in  the  twenty-four-hour  urine.  On  the  other  hand,  urine  collected 
and  examined  at  short  intervals  (every  half  hour)  after  taking  large 
quantities  of  polysaccharide-rich  food  will  frequently  be  found  to  contain 
traces  of  reducing  substances. 

For  practical  purposes  it  has  been  considered  that  an  individual  who 
develops  glycosuria  after;  taking  100  gm.  of  glucose  must  be  considered 
as  at  least  a  potential  diabetic.  In  the  light  of  the  above  results  and 
for  many  other  reasons,  there  is,  however,  considerable  doubt  as  to  the 
value  of  the  assimilation  test.  Thus,  when  a  solution  of  glucose  is 
given  orally,  its  rate  of  absorption  will  depend  very  largely  on  the 
motility  of  the  stomach.  If  this  is  normal,  the  solution  will  very  quickly 
find  its  way  past  the  pyloric  sphincter  into  the  intestine,  where  it  will 
be  rapidly  absorbed.  If,  on  the  other  hand,  the  pyloric  sphincter  does 
not  open  freely,  the  passage  of  the  glucose  into  the  intestine  may  be 
so  delayed  that  no  more  is  present  in  this  place  at  one  time  than  would 
be  the  case  after  an  ordinary  diet  of  polysaccharide.  And  even  after 
the  sugar  solution  enters  the  small  intestine,  differences  in  the  amount 
of  the  intestinal  contents  with  which  it  becomes  mixed,  in  the  extent  of 
bacterial  growth,  and  in  the  absorption  process,  may  very  materially 
affect  the  rate  at  which  the  glucose  gains  entry  to  the  blood. 

Although  often  of  doubtful  diagnostic  value,  determination  of  the 
assimilation  limit  is  of  considerable  aid  in  controlling  the  treatment  of 


'Examination  of  normal  individuals  has  shown  that  the  assimilation  limit  for  different  sugars 
varies  somewhat;  for  glucose  it  appears  to  be  from  about  ISO  to  250  gm.  ;  for  levulose,  which,  it 
will  be  remembered,  is  the  monosaccharide  associated  with  glucose  in  the  construction  of  the  cane- 
sugar  molecule,  the  assimilation  limit  is  frcm  100  to  ISO  gm. ;  for  cane  sugar  or  saccharose  itself 
the  figures  seem  to  vary  considerably,  but  are  given  as  between  50  and  200  gm. ;  for  lactose,  another 
disaccharide,  and  the  sugar  present  in  milk,  the  assimilation  limit  is  distinctly  lower — namely,   100  gm. 


654  MKTABOLISM 

diabetes.  For  this  purpose  the  patient  should  first  of  all  he  instructed 
to  follow  his  usual  diet,  so  that,  by  examination  of  the  amount  of  sugar 
excreted  in  the  urine,  an  opinion  may  he  formed  of  the  severity  of  the 
case.  The  diet  should  then  he  changed  so  as  to  consist  of  a  part  that 
contains  no  carhohydrates  and  another  composed  entirely  of  starchy 
food.  The  former  is  made  up  of  eggs,  fish,  green  vegetables,  fat,  etc., 
and  the  latter,  to  start  with,  should  consist  of  100  grams  of  bread,  dis- 
tributed between  the  two  main  meals  of  the  day,  one  of  which  is  break- 
fast. This  diet  should  be  continued  until  the  glycosuria  either  disappears 
or  attains  a  constant  level.  If  it  disappears,  the  case  is  classified  as  a 
mild  one  of  diabetes,  and  the  daily  allowance  of  bread  may  be  increased, 
by  50  grams  a  day,  until  the  sugar  again  makes  its  appearance  in  the 
urine,  indicating  that  the  assimilation  limit  has  been  reached.  For 
therapeutic  purposes,  the  patient  should  now  be  instructed  to  take  about 
three  fourths  of  this  amount  of  carbohydrate  in  his  daily  rations,  and 
he  should  be  supplied  with  explicit  instructions  in  the  shape  of  diet 
tables  as  to  what  variety  and  quantities  of  the  various  carbohydrate 
materials  his  food  may  contain.  His  urine  should  be  examined  at  fre- 
quent intervals — once  a  week — and  he  should  be  instructed  as  to  the 
nature  of  his  disease  and  the  importance  of  his  remaining  aglycosuric. 
By  further  treatment  such  so-called  latent  cases  of  diabetes  may  be 
kept  in  perfect  health  for  many  years. 

When,  on  the  other  hand,  the  glycosuria  exists  with  100  grams  of 
bread  in  the  daily  ration,  this  must  be  reduced  to  50  grams,  and  if  after 
some  days  the  first  reduction  does  not  suffice  to  render  the  urine  free 
from  sugar,  carbohydrates  must  be  withheld  entirely  from  the  diet. 
If  the  glycosuria  does  not  now  disappear,  the  case  is  to  be  considered 
severe,  and  it  may  be  necessary  to  undertake  the  starvation  treatment, 
which  has  recently  been  developed  in  this  country  by  Allen18  and  Joslin19 
with  apparent  success.  By  the  reduction  of  carbohydrate,  or  by  the 
starvation  treatment,  it  is  usually  possible  to  make  even  the  severest 
cases  of  diabetes  aglycosuric,  and  when  this  has  been  attained,  then 
gradually  to  increase  the  amount  of  protein  or  carbohydrate  food  until 
the  assimilation  limit  has  been  reached. 

Saturation  Limits. — To  avoid  error  caused  by  irregular  absorption  from 
the  intestines,  some  investigators  have  recommended  the  determination 
of  the  assimilation  limit  after  intravenous  or  subcutaneous  injections 
of  sugar.  But  even  this  refinement  in  technic  has  not,  as  a  rule,  had  the 
effect  of  rendering  the  results  of  any  very  evident  value  as  a  criterion 
of  the  utilization  of  glucose  in  the  animal  body.  The  reason  for  this 
unreliability  of  the  method  is  mainly  that  the  period  of  injection  of  the 
glucose  solution  usually  occupies  only  a  few  minutes,  so  that  it  causes 


Till:    METABOLISM    OF   THE   CARBOHYDRATES  655 

a  sudden  instead  of  ;>  very  gradual  increase  in  the  sugar  concentration 
of  the  blood,  the  conditions  being  quite  unlike  those  which  exist  during 
the  normal  absorption  of  glucose  from  the  intestine.  The  mechanism 
by  which  the  body  ordinarily  disposes  of  excessive  amounts  of  glucose 
absorbed  into  the  portal  blood,  is  not  adjusted  to  operate  when  the  sys- 
temic blood  is  suddenly  overcharged  with  this  substance.  In  the  one 
case  the  glucose  is  a  foodstuff;  in  the  other,  because  of  its  excessive 
concentration  in  the  blood,  it  is  more  or  less  of  a  poison.  Such  results,  in 
other  words,  merely  show  us  how  much  glucose  can  be  added  at  one 
time  to  the  organism  without  any  overflow  into  the  urine,  but  they 
furnish  us  with  no  information  regarding  the  power  of  the  organism  to 
utilize  a  constant  though  moderate  excess  of  this  substance.  In  the  one 
case  it  is  the  "saturation  limit,"  in  the  other  the  "utilization  limit"  of 
the  organism  for  glucose,  that  we  are  really  considering. 

Consideration  of  these  principles  has  led  Woodyatt,  Sansum  and  Wil- 
der20 to  undertake  a  thorough  reinvestigation  of  the  whole  problem  of 
the  utilization  or,  as  they  prefer  to  call  it,  the  tolerance  of  the  body  for 
glucose.  They  emphasize  the  obvious  fact  that  the  ability  of  the  organism 
to  utilize  glucose  "must  depend  on  the  rate  at  which  the  tissues  are 
able  to  abstract  it  from  the  blood  by  their  combined  powers,  to  burn  it, 
to  reduce  it  into  fat  or  to  polymerize  it  into  glycogen."  To  form  any 
estimate  of  the  combined  effect  of  these  processes,  we  must  take  into 
account  not  only  the  amount  of  glucose  per  unit  of  body  weight  (grams 
per  kilogram),  but  also  the  rate  of  injection,  for  "tolerance  must  be 
regarded  as  a  velocity,  not  as  a  weight." 

Briefly  summarized,  the  conclusions  which  Woodyatt,  etc.,  have  so  far 
drawn  from  their  investigations  are  as  follows :  In  a  normal  rabbit,  dog, 
or  man,  0.8-0.9  gm.  of  glucose  per  kilogram  body  weight  and  per  hour  can 
be  utilized  by  the  organism  for  an  indefinite  time  without  causing  gly- 
cosuria. When  between  0.8  and  2  gm.  are  injected,  a  part  of  the  excess 
appears  in  the  urine,  steadily  increasing  until  a  maximum  is  reached, 
after  which  the  excreted  fraction  remains  constant  (at  about  one-tenth). 
If  more  than  about  2  grams  per  kilogram  an  hour  are  injected,  "a  large 
percentage  of  all  glucose  in  excess  of  the  2  gm.  per  kilogram  an  hour 
appears  in  the  urine  when  constant  conditions  are  once   established." 

The  fact  that  so  much  glucose  injected  intravenously  can  be  used 
without  the  appearance  of  any  of  it  in  the  urine,  indicates  a  method  by 
which  foodstuffs  may  be  supplied  to  the  tissues  in  cases  where,  on  account 
of  gastrointestinal  disturbances,  it  is  impossible  to  have  food  absorbed 
by  the  usual  pathways.  The  possible  value  of  such  a  method  of  treat- 
ment in  cases  of  extreme  weakness  has  been  tested  on  laboratory  animals 
by  Allen,  who  states  that  such  injection  seems  to  have  a  valuable  nutri- 


656  METABOLISM 

tive  and  strengthening  effect.  He  found,  for  example,  that  in  cats 
starved  to  extreme  weakness  the  injection  of  a  fraction  of  a  gram  per 
kilogram  of  glucose  had  an  unmistakable  strengthening  effect,  and 
sometimes  appeared  to  save  life.  Such  results  would  seem  to  indicate  that 
in  certain  cases  where  blood  transfusion  is  impracticable,  glucose  in- 
fusions should  be  tried.  Subcutaneous  injection  of  sugar,  either  for  the 
purpose  of  determining  the  assimilation  limit  or  with  the  object  of  sup- 
plying foodstuffs  parenterally,  is  impracticable  because  of  the  pain  and 
sometimes  sloughing  produced  at  the  point  of  injection. 

We  have  devoted  no  inconsiderable  space  to  a  discussion  of  assimila- 
tion limits  because  of  the  great  interest  in  diabetic  therapy  which  this 
procedure  has  aroused  during  recent  years.  We  may  now  turn  our 
attention  to  a  closer  analysis  of  the  changes  that  take  place  in  carbohy- 
drates during  their  passage  through  the  animal  body. 

DIGESTION  AND  ABSORPTION 

Digestion. — All  digestible  carbohydrate  taken  with  the  food  is  con- 
verted by  the  digestive  agencies  into  the  monosaccharides,  glucose  and 
levulose,  as  which  it  is  absorbed  into  the  blood  of  the  portal  system. 
To  bring  about  this  resolution  of  carbohydrate  into  monosaccharides, 
several  enzymes  are  employed.  The  first  of  these  is  the  ptyalin  of  saliva. 
It  is  not  a  very  powerful  enzyme,  being  capable  of  acting  only  on  starches 
that  are  in  a  free  state,  i.e.,  not  surrounded  by  a  cellulose  envelope; 
but  even  on  free  starch,  ptyalin  displays  little  of  its  activity  during  the 
time  the  food  is  in  the  mouth.  After  the  food  is  swallowed  and  becomes 
deposited  in  the  fundus  of  the  stomach,  there  is  an  interval  of  time — 
lasting  until  hydrochloric  acid  has  been  secreted  to  such  an  extent  as  to 
permit  some  of  the  acid  to  exist  in  a  free  state — during  which  the  ptyalin 
acts  on  the  starch  of  the  swallowed  food.  During  this  time  the  activity 
of  the  ptyalin  is  actually  assisted  on  account  of  the  fact  that  a  slight 
increase  in  hydrogen-ion  concentration  of  the  digestive  mixture  accel- 
erates the  action  of  ptyalin. 

The  product  of  ptyalin  digestion  is  maltose,  a  disaccharide  composed 
of  two  molecules  of  glucose.  On  entering  the  intestine,  the  carbohydrates 
therefore  exist  partly  as  undigested  starch,  partly  as  glucose,  and  partly 
as  maltose.  In  the  favorable  environment  of  the  duodenum  a  much 
stronger  diastatic  enzyme  called  amylopsin  very  quickly  hydrolyzes  the 
starch  through  dextrine  into  maltose.  The  maltose  derived  from  the 
starch  and  the  unchanged  sugars,  such  as  cane  sugar,  maltose  and  lac- 
tose, which  have  been  taken  with  the  food,  unless  they  are  present  in  very 
high  concentration  in  the  intestinal  contents,  are  not  immediately  ab- 


THE    METABOLISM    OF    THE    CARBOHYDRATES  (i.">7 

sorbed  into  the  blood,  but  become  subject  to  the  action  of  other  enzymes 
contributed  by  the  intestinal  juice  namely,  the  inverting  enzymes,  one 
of  which  exists  Eor  each  of  the  disaccharides.     By  their  action  maltose 

is  converted  into  two  molecules  of  glucose  by  the  enzyme  maltase;  lac- 
tose, into  galactose  and  glucose  by  lactase;  and  cane  sugar,  into  levu- 
lose  and  glucose  by  invertase.  It  is  interesting  to  note  thai  in  animals 
whose  food  does  not  contain  one  of  those  disaccharides,  the  correspond- 
ing inverting  enzyme  is  absent  from  the  intestinal  juice.  The  herbivo- 
rous animals,  for  example,  do  not  take  any  lactose  in  their  food,  and  the 
intestinal  juice  contains  therefore  no  lactase,  although  it  is  present  in 
that  of  the  young  animals  while  still  suckling. 

A  certain  amount  of  carbohydrate  becomes  attacked  by  the  intestinal 
bacteria.  These  split  the  monosaccharides  into  lower  fatty  acids  and 
gases,  such  as  methane  and  carbon  dioxide.  Besides  this  obviously  de- 
structive process,  bacteria  also  perform  a  useful  function  in  the  digestion 
of  carbohydrates,  in  that  certain  strains  of  them  are  able  to  digest  cellu- 
lose, for  -which  no  special  enzyme  is  provided.  Bacterial  digestion  is  con- 
sequently essential  in  herbivorous  animals;  it  takes  place  in  the  cecum, 
which  is  enormously  developed  for  this  purpose  (page  463). 

Absorption. — The  glucose  and  levulose  produced  by  digestion  are 
absorbed  into  the  blood  of  the  portal  system.  When  a  very  large  quan- 
tity of  a  disaccharide,  such  as  cane  sugar,  is  present  in  the  food,  a  certain 
amount  of  the  sugar  is  absorbed  unchanged — that  is  to  say,  as  cane  sugar 
— and  appears  in  the  blood,  from  which,  since  it  is  an  abnormal  con- 
stituent, it  is  excreted  unchanged  in  the  urine.  This  alimentary  glyco- 
suria is  particularly  evident  when  the  sugar  is  taken  without  any  other 
food;  thus,  after  taking  cane  sugar  in  an  amount  corresponding  to  5 
grams  per  kilogram  body  weight,  it  was  found  in  one  and  a  half  hours 
afterward  that  the  urine  of  ten  out  of  seventeen  healthy  individuals  con- 
tained cane  sugar.  The  urine  of  three  of  these  men,  however,  also  con- 
tained invert  sugar — that  is,  dextrose  and  levulose.  Cane  sugar  con- 
tinued to  be  excreted  for  from  six  to  seven  hours. 

The  Sugar  Level  in  the  Blood. — While  no  absorption  of  sugar  is  going 
on,  the  percentage  of  this  substance  in  the  blood  of  the  portal  vein  is  the 
same  as  that  in  the  systemic  circulation.  During  absorption  the  former 
becomes  perceptibly  raised — to  what  extent  we  can  not  say — and  in  the 
latter  a  less  marked  increase  of  sugar  concentration  is  usually  detectable. 
Evidently,  then,  between  the  point  at  which  the  sugar  is  absorbed  and 
the  blood  of  the  systemic  circulation,  some  barrier  exists  which  holds 
back  some  of  the  excess  of  absorbed  sugar.  We  have  very  inaccurate 
information  as  to  how  efficiently  these  barriers  hold  back  the  excess  of 
absorbed  glucose  because  of  the  technical  difficulty  in  collecting  blood 


658 


METABOLISM 


from  the  portal  vein  without  serious  disturbance  to  the  animal.  Indeed, 
the  only  way  by  which  the  problem  has  been  accurately  studied  is  by 
comparing  the  blood  of  the  portal  circulation  with  that  of  the  systemic 
circulation  during  the  injection  of  a  solution  of  dextrose  into  one  of  the 
smaller  branches  of  the  portal  vein.21  In  such  experiments  it  has  been 
found  that  the  percentage  of  sugar  is  a  little  less  in  the  blood  of  the 
abdominal  vena  cava  than  in  that  of  the  portal  vein,  and  is  still  less  in 
the  blood  of  the  systemic  veins,  such  as  the  femoral — results  which  justify 
the  conclusion  that  the  barriers  responsible  for  taking  out  some  of  the 
absorbed  sugar  from  the  blood  exist  in  the  liver  and  in  the  muscles.  The 
curve  in  Fig.  189  will  illustrate  to  what  extent  the  mechanism  operates. 


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Fig.  189. — Curves  showing  the  percentage  of  glucose  in  blood  after  a  constant  injection  of 
an  18  per  cent  solution  into  a  mesenteric  vein.  V.C.,  vena  cava,  continuous  line;  P.D.,  pan- 
creaticoduodenal vein,  broken  line;  /,  iliac,  dotted  line. 


It  will  be  observed  that,  so  far  as  can  be  judged  from  changes  in  the 
concentration  of  sugar  in  the  blood,  the  sugar-retaining  power  of  the 
liver  is  about  equal  to  that  of  the  muscles — a  conclusion  which  is,  how- 
ever, contrary  to  the  usually  accepted  one  that  the  liver  has  such  pro- 
nounced sugar-retaining  powers  that  under  ordinary  circumstances  it 
removes  from  the  portal  blood  all  the  excess  of  sugar  added  to  it  by 
absorption  and  which  is  not  required  by  the  organism. 

One  objection  which  may  properly  be  made  to  these  observations  is 
that  the  animals  oh  which  they  were  made  were  under  anesthesia,  and 
that  the  anesthetic  had  a  paralyzing  effect  on  the  sugar-retaining  power 
of  the  liver.  In  view  of  this  criticism  it  is  important  to  examine  the 
results  obtained  on  animals  that  are  not  under  the  influence  of  anes- 


THE    METABOLISM    OF   THE   CARBOHYDRATES  659 

thesia.  Such  observations  have  been  made  on  rabbits,  and  a  few  on  man 
himself.  By  collecting  blood  from  the  oar  veins  of  rabbits,  it  lias  been 
found  that,  after  giving  from  two  to  ten  grams  of  glucose  by  stomach, 
the  glucose  concentration  of  the  systemic  blood  begins  to  rise  in  fifteen 
minutes,  attaining  a  maximum  in  about  an  hour  and  then  returning  to 
the  normal  level  in  about  three  hours. 

Similar  results  have  been  obtained  by  examination  of  the  venous  blood 
in  man.  After  giving  100  grams  of  glucose  by  mouth,  for  example,  there 
is  commonly  an  increase  in  blood  sugar  amounting  to  from  30  to  34  per 
cent  of  the  normal  and  lasting  for  from  one  to  four  hours.  The  existence 
of  this  postprandial  hyperglycemia,  as  we  may  call  it,  indicates  that  the 
sugar-retaining  powers  of  the  liver  and  muscles  are  not  sufficiently  de- 
veloped to  prevent  the  accumulation  of  some  of  the  absorbed  sugar  in  the 
systemic  blood.  Whenever  this  increase  exceeds  a  certain  limit,  some  of 
the  sugar  begins  to  escape  through  the  kidney  into  the  urine,  producing 
glycosuria — postprandial  glycosuria.  The  percentage  of  blood  sugar  above 
which  glycosuria  occurs  is,  in  the  case  of  man,  probably  about  0.10  to  0.11 
gm.  per  cent.  After  damage  to  the  kidney,  as  in  nephritis,  or  in  long-stand- 
ing cases  of  mild  diabetes,  the  percentage  may  probably  rise  considerably 
higher  in  the  blood  without  evidence  of  glycosuria. 

Value  of  Blood  Examination  in  Diagnosis  of  Diabetes. — The  determina- 
tion of  the  amount  of  ingested  carbohydrate  required  to  bring  about  post- 
prandial glycosuria  constitutes,  as  we  have  already  seen,  the  so-called 
assimilation  limit  for  sugar,  which  is  often  taken  as  an  index  of  the  sugar- 
metabolizing  power  of  the  organism.  It  is  evident,  hoAvever,  that  the  time 
of  onset,  and  the  extent  and  duration  of  postprandial  hyperglycemia  must 
serve  as  a  more  certain  index  of  the  sugar-retaining  power  of  the  liver 
and  muscles ;  and  now  that  a  simple  and  rapid  clinical  method  exists 
(Lewis-Benedict  method)  for  the  accurate  determination  of  sugar  in  small 
quantities  of  blood,  there  is  no  reason  why  this  index  should  not  be  used 
for  the  detection  of  failing  powers  to  metabolize  carbohydrate. 

In  no  disease,  probably  not  even  in  tuberculosis,  is  it  more  important 
than  in  diabetes  that  an  early  diagnosis  should  be  made.  Thus,  if  we  find 
that  the  postprandial  hyperglycemia  after  a  certain  amount  of  carbo- 
hydrate develops  to  an  unusually  high  degree  and  persists  for  an  unusual 
length  of  time,  we  are  justified  in  curtailing  the  carbohydrate  supply  so  as 
to  hold  these  values  down  to  their  level  in  normal  individuals.  It  is  almost 
certain  that  the  first  sign  of  diabetes  is  an  unusual  degree  and  duration 
of  postprandial  hyperglycemia.  At  first  the  excess  of  sugar  leads  to  no 
damage  and  it  is  insufficient  to  cause  any  evident  glycosuria,  although  it  is 
quite  likely  that  if  the  urine  in  such  individuals  were  collected  at  very 
frequent  intervals  after  eating  carbohydrate-rich  food,  glucose  would  be 


fi60  METABOLISM 

found  present  in  at  least  some  of  the  specimens.  In  incipient  diabetes, 
however,  the  condition  progresses,  until  the  postprandial  hyperglycemia 
after  one  meal  has  not  become  entirely  replaced  before  the  next  is  taken, 
so  that  the  increase  in  sugar  produced  by  the  second  meal  becomes  super- 
added on  that  following  the  first  meal.  The  curve  of  blood  sugar  rises 
ever  higher  and  higher,  until  at  last  permanent  hyperglycemia  is  estab- 
lished, or  rather  the  normal  level  from  which  the  postprandial  rise  occurs 
has  become  permanently  raised,  so  that  in  blood  collected  at  any  time  a 
higher  percentage  of  sugar  is  found. 

The  Relationship  Between  the  Sugar  Concentration  of  the  Blood  and 
the  Occurrence  of  Glycosuria. — Claude  Bernard  first  pointed  out  that  the 
percentage  of  sugar  in  the  blood  may  rise  considerably  above  its  normal 
level  without  the  appearance  of  any  of  the  sugar  in  the  urine,  or  at  least 
without  a  sufficient  amount  to  give  the  usual  tests  for  sugar.  Even  when 
this  limit  is  reached,  as  Ave  have  seen,  the  sugar  which  appears  is  not  all  of 
the  excess  but  only  a  small  part  of  it.  This  overflow  hypothesis,  as  it  is 
called,  has  not  been  universally  accepted  because  of  the  many  results 
which  are  not  in  conformity  with  it.  Many  of  these  exceptional  results 
have  been  explained  as  due  to  alterations  in  the  permeability  of  the  kidney 
for  sugar,  and  in  general  it  is  probably  safe  to  accept  Claude  Bernard's 
hypothesis  with  certain  reservations. 

Strong  support  has  been  lent  to  a  modified  form  of  the  hypothesis  by 
the  recent  work  of  "Woodyatt  and  his  collaborators,  who  have  shown  by 
continuous  intravenous  glucose  injections  that  as  much  as  0.8  gm.  of 
glucose  per  kilo  body  weight  can  be  injected  during  an  hour  into  an 
animal  without  any  glycosuria,  although  under  such  conditions  a  very 
distinct  increase  occurs  in  the  percentage  of  sugar  in  the  blood. 

To  explain  the  failure  of  glucose  to  pass  into  the  urine  under  normal 
conditions,  it  has  been  supposed  by  several  investigators  that  the  glucose 
exists  in  some  form  of  chemical  combination  in  the  blood.  This  compound 
is  believed  to  behave  like  a  colloid.  One  of  the  recent  supporters  of  this 
view  is  Allen,  who  has  observed  that,  when  glucose  is  injected  intrave- 
nously, it  causes  diuresis  as  well  as  glycosuria;  whereas  glucose  injected 
subcutaneously  or  taken  by  mouth  causes  neither  of  these  conditions  to 
become  developed ;  indeed  it  causes  for  some  time  after  the  administration 
of  the  sugar  a  distinct  anuria.  To  explain  these  differences  in  behavior 
between  glucose  administered  intravenously  and  that  taken  in  other  ways, 
it  is  supposed  that  the  glucose  molecule  in  passing  through  the  intervening 
wall  of  the  capillaries  combines  with  some  substance  to  form  a  compound 
which  becomes  available  for  incorporation  into  and  utilization  by  the 
tissues,  glucose  in  a  free  state  being  incapable  of  utilization.  This  com- 
pound is  supposed  to  be  of  a  colloidal  nature,  and  the  substance  which 


Till:    MKTAI50USM    OF    TIIK    t'AHliOH YDKATES  661 

combines  with  glucose  to  Eorm  it  is  believed  to  be  related  to  the  internal 

secretion  of  the  pancreas  (sec  page  <i7(ii. 

The  difficulty  in  explaining  why  the  glucose  of  the  blood  does  not  con- 
stantly leak  into  the  kidney  is,  however,  the  only  evidence  Upon  which  the 
hypothesis  of  a  blood  sugar  compound  rests.  No  chemical  evidence  can 
be  offered  in  support  of  such  a  view.  On  the  contrary,  all  experimental 
work  indicates  that  the  sugar  exists  in  a  free  state;  but  unfortunately  even 
tins  evidence  is  not  convincing.  Thus,  it  has  been  found  that,  when  speci- 
mens of  perfectly  fresh  blood  are  placed  in  a  series  of  dialyzer  sacs  sus- 
pended in  isotonic  saline  solutions,  each  solution  containing  a  slightly  dif- 
ferent percentage  of  glucose,  diffusion  of  glucose,  in  one  or  other  direction, 
occurs  in  all  of  them  save  one — namely,  that  in  which  the  percentage  of 
glucose  in  the  fluid  outside  the  dialyzer  is  exactly  equal  to  the  total  sugar 
content  of  the  blood.  Such  a  result  can  be  explained  only  by  assuming  that 
all  of  the  sugar  in  the  blood  exists  in  a  freely  diffusible  state.  In  its  general 
nature  this  experiment  is  analogous  to  that  by  which  the  tension  or  partial 
pressure  of  C02  is  determined  in  blood  (see  page  338). 

It  has  been  assumed  by  many  clinicians  that  glycosuria  may  sometimes 
become  developed  because  the  kidney  fails  to  hold  back  the  blood  sugar 
even  when  the  percentage  is  not  above  the  normal — so-called  renal  dia- 
betes. For  the  diagnosis  of  this  condition  a  comparison  must  be  made  be- 
tween the  sugar  concentration  of  the  blood  and  that  of  the  urine.  In  order 
to  do  this  at  least  two  samples  of  blood  must  be  taken,  one  of  them  a.t  the 
beginning  and  the  other  at  the  end  of  a  period  during  which  urine  is  being 
collected.  Merely  to  find  that  one  sample  of  blood  collected  before  or  after 
or  during  the  period  of  urine  collection  contains  a  normal  percentage  of 
sugar,  does  not  necessarily  indicate  that  at  some  other  period  while  the 
urine  was  being  produced  a  temporary  hyperglycemia  may  not  have  ex- 
isted. 


CHAPTER  LXXV 
THE  METABOLISM  OF  THE  CARBOHYDRATES  (Cont'd) 

FATE  OF  ABSORBED  GLUCOSE.     GLUCONEOGENESIS 

We  may  now  consider  what  becomes  of  the  sugar  that  is  retained  by 
the  liver  and  muscles.  Two  things  may  happen  to  it:  It  may  become 
stored,  or  it  may  become  oxidized  or  split  up.  Of  these  processes,  storage 
occurs  in  both  the  liver  and  muscles,  whereas  oxidation  occurs  mainly  if 
not  entirely  in  the  muscles,  although  a  certain  amount  of  splitting  of  the 
glucose  molecule  may  also  occur  in  the  liver. 

Storage  of  Sugar. — For  the  present  we  shall  consider  the  process  of 
storage  of  sugar  and  defer  a  consideration  of  its  utilization  until  after  we 
have  studied,  not  only  the  nature  of  the  process  by  which  the  storage 
occurs,  but  also  the  immediate  destiny  of  the  stored  sugar.  The  storage 
of  sugar  by  the  liver  is  brought  about  by  its  conversion  into  a  polysac- 
charide called  glycogen.  After  an  animal  has  been  absorbing  large  quan- 
tities of  glucose,  an  acidified  watery  extract  of  a  portion  of  liver  mad'1 
immediately  after  death  will  be  found  to  contain  no  more  sugar  than  that 
of-  a  normal  liver.  On  the  other  hand,  it  will  be  observed  that  the  extract 
is  highly  opalescent  and  yields  on  the  addition  of  alcohol  a  copious  precip- 
itate, which  on  further  purification  can  readily  be  shown  to  consist  of  a 
polysaccharide — that  is  to  say,  of  a  starch-like  substance  which  on  hydrol- 
ysis with  mineral  acid  becomes  entirely  converted  into  sugar.  If  instead 
of  removing  the  liver  immediately  after  death,  it  is  allowed  to  stand  for 
some  time,  the  yield  of  glycogen  will  greatly  diminish,  and  in  its  place 
Mali  appear  large  quantities  of  glucose,  indicating  that  some  enzyme  must 
exist  which  attacks  the  glycogen  after  death  and  converts  it  into  sugar 
This  enzyme  is  called  glycogenase.  The  existence  of  postmortem  glyco- 
genolysis,  as  it  is  called,  would  seem  to  indicate  that  during  life  also  there 
is  a  constant  tendency  for  the  glycogen  in  the  liver  to  be  attacked  by 
glycogenase,  but  that  this  is  prevented  by  conditions  which  depend  on  the 
vital  integrity  of  the  liver  cell.  It  is  evident  that  if  anything  should 
happen  during  life  to  interfere  with  this  inhibiting  influence,  the  glycogen 
will  become  converted  into  glucose,  which  on  escaping  into  the  blood 
will  produce  hyperglycemia  and  glycosuria. 

Sources  of  Glycogen. — In  studying  the  source  of  sugar  in  the  animal 
body  it  is  important  therefore  that  we  should  first  of  all  know  exactly  the 

662 


THE    METABOLISM    OF    THE   CARBOHYDRATES  663 

conditions  under  which  glycogen  may  be  formed  in  the  liver;  that  is, 
whether  il  is  formed  from  absorbed  sugar  alone,  or  from  other  substances 
also,  such  as  protein  and  fat.  The  importance  of  such  knowledge  rests 
in  the  fad  thai  in  severe  diabetes,  sugar  still  continues  to  be  added  to 
the  blood,  although  no  sugar  is  being  taken  with  the  food.  To  check  the 
hyperglycemia  in  such  cases  it  becomes  necessary,  therefore,  to  curtail 
the  diet  not  only  with  regard  to  its  carbohydrate 'content,  but  also  with 
regard  to  whatever  other  foodstuff  may  be  capable  of  causing  glycogen 
formation.    The  practical  question  therefore  is,  What  are  these  foodstuffs? 

There  are  two  methods  by  which  the  problem  may  be  investigated.  The 
first,  which  Ave  may  call  the  direct  method,  consists  in  rendering  the  liver 
free  of  glycogen  and  then  some  time  afterward  feeding  the  animal  with 
the  foodstuff  in  question,  afterward  killing  it  and  examining  the  liver 
for  glycogen.  The  other,  which  we  may  call  the  indirect  method,  con- 
sists in  first  of  all  rendering  the  animal  incapable  of  oxidizing  glucose — 
that  is,  making  it  diabetic — and  then  proceeding  to  see  whether  the  in- 
gestion of  a  given  foodstuff  causes  an  increase  in  the  sugar  excretion  in 
the  urine.  The  methods  for  rendering  an  animal  experimentally  diabetic 
Avill  be  considered  later;  for  the  present  it  is  important  to  note  that,  if 
a  diabetic  animal  excretes  more  glucose  while  fed  on  a  given  foodstuff, 
we  may  infer  that  the  normal  animal  would  convert  it  into  glycogen. 

The  results  of  the  direct  method  are  much  less  reliable  than  those  of 
the  indirect  for  the  reason  that  it  is  extremely  difficult  to  remove  all 
traces  of  glycogen  from  the  liver.  The  methods  employed  for  this  pur- 
pose have  consisted  in:  (1)  starvation  of  the  animal;  (2)  muscular  ex- 
ercise; (3)  exercise  and  starvation  combined;  and  (4)  the  production  of 
certain  forms  of  experimental  diabetes — for  example,  that  produced  by 
phlorhizin.  Starvation  alone  is  unsatisfactory,  for  it  has  been  found 
that,  although  at  certain  stages  of  this  condition  the  liver  may  become  al- 
most entirely  free  from  any  trace  of  glycogen,  at  a  later  stage  glycogen 
may  again  make  its  appearance.  It  is  therefore  most  difficult  to  decide 
at  what  stage  in  starvation  the  animal  should  be  considered  as  glycogen- 
free. 

If  the  starving  animal  is  made  to  perform  muscular  exercise,  complete 
removal  of  glycogen  from  the  liver  can  be  depended  upon.  The  exercise 
may  be  produced  by  the  administration  of  strychnine  in  such  dosage  as 
just  to  produce  convulsions  of  the  voluntary  muscles  without  permanent 
contraction  of  those  of  respiration.  The  most  useful  method,  however, 
consists  in  starving  the  animal  for  a  few  days  and  then  placing  it  in  a 
cold,  damp  room,  after  giving  it  a  cold  bath.  The  evaporation  of  mois- 
ture from  the  surface  so  cools  the  body  down  that  the  glycogen  store  all 
becomes  used  up  in  the  attempt  to  supply  fuel  for  the  production  of 


664  METABOLISM 

sufficient  heat  to  maintain  the  body  temperature.  This  method  can  he 
rendered  still  more  certain  in  effecting  a  removal  of  all  carbohydrate 
from  the  body  by  giving  the  animal  phlorhizin  every  eight  hours.  This 
drug,  as  Ave  shall  see,  renders  the  animal  diabetic. 

After  removing  the  glycogen,  further  deposition  in  the  liver  can  be 
readily  shown  to  occur  when  any  of  the  ordinary  sugars  or  starches  are 
given  as  food.  It  does  not  occur,  however,  when  chemical  substances 
closely  related  to  ordinary  sugar,  such  as  the  wood  sugars  (pentoses) 
or  the  alcohols  and  acids  corresponding  to  dextrose,  are  contained  in  the 
diet.  Nor  does  it  occur  with  cellulose  or  with  inulin,  a  polysaccharide 
built  up  from  pentose  sugar.  When  proteins  are  fed  the  results  are  not 
so  definite,  although  many  observers  have  claimed  that  glycogen  is 
formed.  With  fat,  on  the  other  hand,  no  glycogen  formation  can  be 
shown  to  occur,  although  we  knoAV  that  a  trace  of  carbohydrate  must  be 
formed  out  of  the  glycerine  of  the  fat  molecule. 

The  results  of  the  direct  method,  even  when  the  conditions  are  per- 
fectly controlled,  are  very  unreliable,  because  any  new  sugar  produced 
by  the  ingested  substance  instead  of  being  stored  as  glycogen  may  be 
directly  used  by  the  tissues  as  it  is  formed.  Where  only  a  slight  degree 
of  gluconeogenesis  is  occurring,  it  is  not  likely  that  any  of  the  glucose 
will  be  retained  in  the  body  as  glycogen. 

The  methods  employed  for  producing  experimental  diabetes  in  investi- 
gation of  these  problems  by  the  indirect  method  are  (1)  the  entire  removal 
of  the  pancreas,  and  (2)  the  continuous  administration  of  the  drug 
phlorhizin.  The  animal  rendered  diabetic  by  either  of  these  methods  is 
first  of  all  observed  for  several  days  to  determine  the  normal  daily  ex- 
cretion of  sugar.  At  the  same  time  the  nitrogen  excretion  for  the  day 
is  determined,  the  ratio  between  the  total  nitrogen  and  the  glucose  being 
known  as  G  to  N  ratio,  and  being  about  1  to  3.65  when  complete  diabetes 
has  become  established.  The  foodstuff  in  question  is  then  fed  to  the 
animal,  and  the  amount  of  extra  glucose  excreted  thereby  is  taken  to 
represent  that  which  has  been  derived  from  the  ingested  food.  By  this 
method  it  has  been  possible  to  show  that,  not  only  the  above  mentioned 
carbohydrates,  but  protein  as  well  produce  a  very  considerable  quan- 
tity of  glucose  in  the  animal  body.  Fats,  however,  yield  only  negative 
results. 

The  indirect  method  has  another  great  advantage  over  the.  direct  in 
that  the  results  are  much  more  quantitative  in  character;  for  example, 
Lusk  and  his  pupils  have  been  able  to  determine  the  amount  of  glucose 
which  can  be  produced  by  feeding  certain  of  the  building  stones  of  the 
protein  molecule.     The   great  practical   importance   of  such  results  in 


THE    METABOLISM    OP   THE   CARBOHYDRATES  665 

the  therapy  of  diabetes  makes  it  advisable  for  us  to  go  into  the  subject 
a  little  more  in  detail  here. 
Dogs  are  rendered  diabetic  by  phlorhizin   followed  by  a  eold  bath 

and  exposure  in  a  cold  room.  When  all  of  the  original  glycogen  in  the 
body  has  been  gol  rid  of,  as  evidenced  by  the  constancy  of  the  G  to  X 
ratio  in  the  daily  quantities  of  urine  excreted,  the  substance  under  in- 
vestigation is  fed.  If  this  substance  contains  no  nitrogen  and  causes  no 
change  in  the  nitrogen  excretion,  any  increase  in  that  of  glucose  must 
obviously  represent  the  extent  to  which  the  substance  has  become  con- 
verted into  this  sugar.  On  the  other  hand,  if  the  substance  itself  con- 
tains nitrogen,  or  if  it  causes  a  change  in  the  excretion  of  nitrogen,  it 
becomes  necessary  to  calculate  how  much  of  the  excreted  glucose  might 
have  been  derived  from  the  body  protein,  assuming  that  this  can  form 
glucose,  and  how  mind)  from  the  administered  substance.* 

From  the  results  of  this  method  it  has  been  an  easy  matter  to  show 
that  the  following  substances  are  converted  in  the  animal  body  into 
glucose:  (1)  Glycol  aldehyde  (CH2OH-CHO).  By  placing  three  mol- 
ecules of  this  substance  together,  a  hexose  molecule  will  be  produced, 
a  synthesis  which  can  be  accomplished  in  the  chemical  laboratory. 
Glycol  aldehyde  may  be  formed  in  normal  metabolism  out  of  glycocoll 
(CH2NH2C00H). 

(2)  Glycerol  (CILOH  -  CHOH  -  CH2OH)  may  also  readily  be  con- 
verted into  hexose  in  the  laboratory,  the  possible  intermediary  products 
being  dioxyacetone  (CH2OH  -  CO  -  CH2OH)  and  glyceric  aldehyde 
(CH2OH-CHOH-CHO).  Two  molecules  of  either  of  these  may  be 
polymerized  to  form  a  hexose  molecule,  and  when  this  process  occurs 
in  the  animal  body,  the  hexose  formed  is  glucose. 

(3)  Lactic  acid  (CH3CHOH  -  COOH)  is  completely  converted  to  dex- 
trose in  the  diabetic  animal,  and  the  process  must  involve  both  a  re- 
arrangement of  the  molecule  and  subsequent  polymerization.  The  related 
substance,  propyl  alcohol  (CH3  -  CH2  -  CH2OH)  is  also  converted  into 
glucose  in  the  phlorhizinizecl  dog.  As  to  the  exact  nature  of  the  chemical 
changes  which  occur  as  intermediary  steps  in  the  conversion  of  these 
substances  into  glucose,  Ave  are  not  as  yet  certain,  but  a  step  has  been 
made  in  the  discovery  that  a  substance  called  methylglyoxal  (CH3COCHO) 
may  be  obtained  from  lactic  acid  and  also  from  glucose,  and  that  this 
substance  is  converted  into  glucose  when  it  is  administered  to  phlorhi- 
zinized  dogs.      We   shall  find  later   an   important   role  for  this  substance 

•This  calculation  is  made  as  follows:  The  amount  of  nitrogen  in  the  administered  substance  is 
deducted  from  the  nitrogen  excretion,  and  the  difference,  which  must  represent  the  nitrogen  of  the 
body  protein,  is  multiplied  by  the  G  to  X  ratio  which  prevailed  on  the  day  previous  to  that  on 
which  the  substance  was  fed.  We  obtain  in  this  way  the  glucose  derived  from  the  bodv.  The 
glucose  coming  from  the  administered  substance  can  then  be  ascertained  by  deducting  that'  derived 
from  the  body  protein  from  the  total  glucose  excretion. 


666  METABOLISM 

in  the  case  of  fat  metabolism,  and  it  can  also  readily  be  produced  during 
the  intermediary  breakdown  of  certain  of  the  protein  building-stones, 
such  for  example  as  alanine  (CH3CHNH,C00H). 

These  chemical  possibilities  regarding  the  nature  of  the  substances 
that  serve  as  stepping  stones  between  the  above  sugar-forming  sub- 
stances and  sugar  itself  may  be  translated  later  into  probabilities  on 
account  of  the  discovery  that  the  enzymes  exist  in  various  tissues  which 
are  involved  in  converting  methylglyoxal  into  lactic  acid: 

CH3  CH, 

I  I" 

CO  +        H2  — >  HCOH 

I  0'«-      | 

CHO  COOH 

(methylglyoxal)  (lactic  acid) 

These  enzymes  are  called  glyoxalases,  and  since  the  reactions  which 
they  mediate  are  undoubtedly  reversible  in  character,  it  is  probable  that 
the  conversion  into  sugar  of  lactic  acid  and  alanine— to  take  those  two 
as  among  the  commonest  of  the  sugar  precursors  of  the  animal  body — 
occurs  according  to  the  following  equation: 

CH3CHNII,COOH  v 

(alanine)  CH.COCHO  — »  C,H12Oe 

CH,CHOHCOOH    /* 

(lactic  acid)  (methylglyoxal)    (hexose) 

The  unique  position  of  methylglyoxal,  besides  explaining  the  known 
resolutions  of  protein  and  fat  and  carbohydrate  in  intermediary  metab- 
olism, is  also  of  importance  in  explaining  the  synthetic  production  of 
glucose  from  fructose  (or  levulose).  Fructose  will  first  of  all  become 
converted  into  methylglyoxal  radicles,  and  these  will  then  become  syn- 
thesized into  glucose. 

The  theory  of  the  conversion  of  glucose  into  lactic  acid  as  a  stepping 
stone  in  the  metabolism  of  carbohydrate  meets  with  one  objection; 
namely,  that  the  lactic  acid  is  not  produced  from  carbohydrate  in  the 
organism,  except  in  cases  where  there  is  oxygen  deficiency  or  excess  of 
alkali  in  the  tissue  fluids. 

Coming  now  to  the  amino  acids,  which,  it  will  be  remembered  repre- 
sent the  building  stones  of  the  protein  molecule,  it  has  been  found  that 
glycocoll,  alanine,  and  aspartic  and  glutamic  acids  increase  the  glucose 
excretion  when  given  to  phlorhizinized  dogs,  whereas  leucine  and  tyro- 
sine have  no  such  action.  By  the  method  described  above,  it  is  possible 
to  determine  the  exact  proportion  of  the  carbon  of  each  of  those  amino 
acids  which  becomes  converted  to  glucose.  This  is  shown  in  the  accom- 
panying table. 


THE    METABOLISM    OF    THE    CARBOHYDRATES 


GG7 


r\  Grams  of  the  Various  Amino  Bodies  Were  Given  to 
Phlorhizin-diabetio  Dogs 


A(ll>    A\H    PORM1    I.A 

AVERAGE  AMOUNT 
OF  GLUCOSE  PRO- 
DUCED  IN   BODY 

PROBABLE                  GLUCOSE  TUAT 
CHANGE                    WOULD  BE  PRO- 
D  BY  CHANGE 

Glycocoll 
CHjNHjCOOH 

13.43     (five     dogs, 
one   gave   15.77) 

All  C  converted             1G.00 
to  glucose 

i.  alanine 

CH3CHNH2COOH 

L8.77    (two  dogs) 

"                             20.22 

Aspartic  acid 
COOH— CII—CIINII— COOH 

12.42    (four    dogs) 

Three  of  the  four         13.52 
C  atoms  converted 
to  glucose 

Glutamic  acid 
COOH 

/ 
CH2 

13.31 

Three  of  the  five             12.24 
C  atoms  converted 
to  glucose 

CH  —  CHNH, 

COOH 

It  is  of  further  interest  to  point  out  that  these  four  amino  acids 
constitute  about  26  per  cent  of  all  the  amino  acids  in  flesh  protein,  and 
that  the  total  yield  of  glucose  from  them  could  be  26.3  grams;  thus 
accounting  for  nearly  one  half  of  the  66  grams  which  a  diabetic  animal 
produces  from  100  grams  of  flesh. 

Gluconeogenesis  in  Normal  Animals. — Although  it  has  been  clearly 
shown  by  the  indirect  method  that  not  only  protein  but  its  decomposi- 
tion products  as  well,  can  be  readily  converted  into  glucose,  yet  this  does 
not  necessarily  indicate  that  a  similar  conversion  occurs  in  the  nondia- 
betic  animal.  That  such  is  the  case,  however,  can  be  shown  in  various 
ways.  Thus,  at  the  end  of  a  period  of  long  starvation  considerable 
quantities  of  glycogen  are  quite  commonly  found  in  the  body,  and  the 
blood  sugar,  although  lower  than  normal,  never  entirely  disappears. 
Noav,  since  no  carbohydrate  is  being  ingested,  and  the  body  stores  of  this 
foodstuff  become  exhausted  early  during  starvation  (cf.  page  663),  it 
is  evident  that  the  carbohydrate  must  be  produced  from  the  protein  of 
the  animal's  body.  A  still  more  convincing  experiment  can  be  con- 
ducted by  producing  strychnine  convulsions  in  a  starving  animal.  If 
the  animal  is  killed  after  the  convulsions  have  lasted  for  a  certain  time, 
the  tissues  will  be  found  almost  if  not  entirely  free  of  glycogen, 
but  if  the  convulsions  are  made  to  disappear  by  giving  chloral  and  the 
animal  allowed  to  sleep  for  some  time  before  killing  it,  glycogen  again 
accumulates  in  the  body.  This  glycogen  must  have  been  manufactured 
out  of  noncarbohydrate  material. 

Corroborative  evidence  of  a  somewhat  different  nature  is  furnished  by 


668  METABOLISM 

an  examination  of  the  respiratory  quotient,  which,  it  "will  be  remem- 
bered (page  54.7),  varies  according  to  the  nature  of  the  foodstuff  or  body 
constituent  that  is  undergoing  metabolism  at  the  time,  being  about  1 
with  carbohydrate  and  about  0.7  with  protein.  If  the  quotient  is 
observed  during  starvation,  it  will  often  be  found  to  fall  below  0.7,  a 
figure  which  can  be  explained  only  by  assuming  that  oxygen  has  been 
retained  in  the  body  beyond  the  quantity  which  is  necessary  for  imme- 
diate purposes  of  oxidation  (cf.  equations  on  page  548). 

Since  it  is  known  that  this  retained  oxygen  can  not  exist  in  the  body 
in  a  free  state  it  must  be  concluded  that  it  has  become  incorporated 
into  substances  having  a  high  oxygen  content.  Such  would  be  the  case 
if  protein  or  fat,  which  contains  only  from  12  to  20  per  cent  of  oxygen, 
were  converted  to  carbohydrate,  which  contains  about  53  per  cent. 
Utilization  of  inhaled  oxygen  for  this  purpose,  as  we  have  seen,  becomes 
very  striking  in  the  case  of  hibernating  animals  during  the  winter  sleep. 


CHAPTER  LXS  V  I 

THE  METABOLISM  OF  THE  CARBOHYDRATES  (Cont'd) 
FATE  OF  GLYCOGEN 

Having  become  familial-  with  the  sources  from  which  glycogen  may 
be  derived,  we  may  now  proceed  to  study  the  fate  of  the  glycogen  found 
in  the  liver  cells  and  in  the  muscles.  For  the  presenl  we  shall  confine  our 
attention  to  the  glycogen  of  the  liver.  If  a  portion  of  liver  removed 
from  a  well-fed  animal  is  examined  microscopically  after  staining  either 
with  iodine  or  with  carmine  by  Best's  method,  it  will  he  found  that  the 
cells  of  the  lobules  are  filled  with  glycogen  except  for  the  nuclei,  which 
are  free  from  this  substance.  If,  on  the  other  hand,  the  liver  is  from  an 
animal  that  has  not  been  recently  fed,  the  lobules  will  contain  no  glyco- 
gen except  for  an  area  bordering  on  the  central  vein  and  perhaps  a 
narrow  strip  at  the  periphery  of  the  lobule.  When  it  is  present  the  rela- 
tive amount  of  glycogen  in  different  lobules,  as  determined  chemically, 
is  the  same  over  the  entire  liver — that  is  to  say,  no  one  lobe  is  richer  in 
this  substance  than  another.  Nothing  definite  is  known  as  to  how  the 
glycogen  is  held  in  the  protoplasm  of  the  cells,  although  some  histolo- 
gists  suggest  that  it  is  combined  with  a  sustentacular  material  especially 
provided  for  this  purpose.  '  ■ 

The  glycogen  stored  in  the  liver  is  gradually  given  up  to  the  blood  of 
the  hepatic  vein  at  such  a  rate  as  to  maintain  in  the  blood  of  the  sys- 
temic circulation  a  more  or  less  constant  percentage  of  glucose.  Under 
ordinary  conditions  this  process  of  glycogenolysis  is  relatively  slow,  but 
when  the  requirements  of  the  organism  for  fuel  become  increased,  as 
during  muscular  exercise,  it  becomes  very  rapid.  The  glycogenic  func- 
tion of  the  liver  appears  therefore  to  exist,  in  part  at  least,  for  the 
purpose  of  preventing  the  flooding  of  the  blood  of  the  systemic  circu- 
lation with  excess  of  sugar  during  absorption  from  the  intestine  and  of 
maintaining  the  normal  percentage  at  other  times.  This  function  is 
analogous  to  that  occurring  in  plants,  in  which  the  sugar  produced  in 
the  leaves,  if  not  immediately  required,  is  transported  to  various  parts 
of  the  plant  and  there  converted  into  starch,  which,  when  the  plant 
requires  it,  as  during  new  growth,  may  again  become  transformed  into 
glucose. 

The    agency   converting   the    glycogen    into    glucose    is   the    diastatic 

669 


670  METABOLISM 

enzyme  glyeogenase,  which  is  present,  not  only  in  the  liver  cell,  but 
also  in  the  blood  and  lymph.  It  is  a  difficult  matter  to  explain  why 
glycogen  should  be  able  to  exist  at  all  in  the  liver  cells  in  the  presence 
of  this  powerful  enzyme.  The  following  possibilities  may  be  considered: 
(1)  That  glyeogenase  does  not  really  exist  in  the  living  liver  cells,  but 
is  a  postmortem  product;  (2)  that,  although  present,  glyeogenase  is  pre- 
vented from  acting  on  the  glycogen  in  the  living  liver  cell  on  account  of 
the  latter  being  protected  from  its  influence  by  combination  with  the 
sustentacular  substance;  or  (3)  that  some  chemical  substance  in  the  liver 
cell  prevents  the  glycogenaEe  from  acting  on  the  glycogen — an  anti- 
glycogenase.  Since  the  removal  of  any  one  of  these  inhibiting  influ- 
ences would  cause  glycogenolysis  to  become  excessive,  and  so  bring 
about  hyperglycemia,  it  is  important,  in  searching  for  the  possible 
causes  of  this  condition,  to  examine  the  evidence  that  has  been  brought 
forward  in  support  of  each  of  these  views. 

Against  the  view  that  glyeogenase  is  a  postmortem  product  may  be 
cited  the  very  rapid  conversion  into  glucose  that  occurs  when  glycogen 
is  added  to  living  blood,  as  by  injecting  some  into  a  vein.  On  account  of 
the  active  glycogenolytic  action  of  blood,  it  has  been  suggested  that 
during  life  glycogen  does  not  become  transformed  into  glucose  until 
after  it  has  been  discharged  into  the  blood  from  the  liver  cell.  "When 
increased  sugar  must  be  mobilized,  glycogen  passes  unchanged,  or  per- 
haps as  some  dextrine,  into  the  blood  and  lymph  of  the  liver  capillaries 
and  lymphatics,  the  glyeogenase  of  which  converts  it  into  glucose,  the 
conversion  being  so  rapid  that,  by  the  time  the  blood  has  traveled  from 
the  liver  through  the  heart  and  pulmonary  vessels  to  the  arteries,  all 
the  glycogen  has  already  become  transformed  into  glucose.  Postmortem 
glycogenolysis,  according  to  this  view,  is  due  to  the  opposite  occur- 
rence— the  transference  of  glyeogenase  from  the  blood  into  the  liver 
cell.  Some  facts  supporting  this  view  are  as  follows:  (1)  It  has  been 
found  that  the  amount  of  free  glucose  in  the  blood  of  the  vena  cava 
is  sometimes  less  than  in  that  collected  simultaneously  from  the  carotid 
artery.  (2)  After  giving  certain  substances,  such  as  phosphorus  or 
peptone,  there  is  distinct  diminution  in  the  amount  of  glycogen  in  the 
liver,  accompanied,  however,  by  no  increase  in  the  amount  of  glucose 
in  the  blood.  And  (3)  if  the  liver  of  an  animal  that  has.  been  rendered 
diabetic  by  stimulation  of  the  splanchnic  nerve  or  by  puncture  of  the 
floor  of  the  fourth  ventricle  is  examined  microscopically,  after  staining 
by  the  carmine  method,  masses  of  stained  glycogen  can  be  found  present 
in  the  capillaries  (sinusoids)  that  lie  among  the  liver  cells. 

According  to  the  second  view,  the  glycogen  is  removed  from  the 
influence  of  the  intrahepatic  glyeogenase  on  account  of  its  combination 


'NIK    MKTAHOIJSM    OF    TlIK    CAKI:<  IHYDRATES  671 

with  a  sustentacular  material.  By  disrupting  this  combination  ;m<l  thus 
exposing  the  glycogen  to  the  action  of  glycogenase,  glycogenolysis  will 

occur:  We  may  call  this  the  mechanical  hypothesis  and  it  deserves 
serious  consideration,  for  it  lias  been  shown  that  very  little  postmortem 
glycogenolysis  occurs  in  the  intact  liver  of  frogs  in  winter, — even  though 
at  this  time  the  organ  contains  an  excess  of  glycogen, — but  becomes 
marked  when  the  liver  is  broken  down  by  mechanical  means. 

The  third  view  depends  on  the  well-known  fact  that  enzyme  activities 
become  most  markedly  altered  by  slight  changes  in  the  chemical  nature 
of  the  environment  in  which  they  act,  Diastatic  enzymes  are  partic- 
ularly susceptible  to  the  reaction  (CH)  of  their  environment,  a  very 
slight  degree  of  acidity  favoring  and  a  trace  of  alkalinity  markedly 
depressing  their  activities.  That  a  tendency  to  increasing  acidity  in 
the  liver  cells  may  retard  the  formation  of  glycogen  is  suggested  by 
the  depressing  effect  produced  on  the  assimilation  limit  of  sugars  by 
administering  acids,  and  by  the  observation  that  postmortem  glycogen- 
olysis becomes  marked  in  proportion  as  the  dying  liver  becomes  acid  in 
reaction.  It  might  be  thought  then  that  glycogenolysis  in  the  liver  cell 
could  be  set  up  by  the  local  production  of  a  certain  amount  of  acid. 
Such  a  liberation  of  free  acid  could  be  brought  about  by  a  curtailment 
in  the  arterial  blood  supply  of  the  hepatic  cell,  producing  a  local  accu- 
mulation either  of  carbonic  or  of  other  less  completely  oxidized  acids 
(e.g.,  lactic).  It  may  be  that  asphyxia  causes  hyperglycemia  by  such 
a  mechanism.  Vasoconstriction  and  consequent  curtailment  of  arterial 
blood  supply  occurs  in  the  liver  when  the  hepatic  nerves  are  stimulated, 
and  it  is  possible  that  the  glycogenolysis  which  is  also  set  up  by  such 
stimulation  is  due  to  the  appearance  of  acids.  The  accelerating  effect 
of  epinephrine  on  glycogenolysis  might  also  be  explained  as  due  to 
limitation  of  blood  supply  on  account  of  vasoconstriction. 

THE  REGULATION  OF  THE  BLOOD  SUGAR  LEVEL 

The  level  at  which  the  concentration  of  sugar  in  the  systemic  blood 
is  maintained  represents  the  balance  between  two  opposing  factors:  (1) 
the  consumption  of  glucose  bv  the  tissues,  and  (2)  the  production  of 
glucose  by  the  liver.  Since  this  is  the  most  readily  oxidizable  of  all 
the  proximate  principles  of  food  (page  652),  muscular  activity  causes 
large  quantities  of  it  to  be  consumed,  so  that  its  concentration  in  the 
blood  tends  to  fall  below  the  physiologic  level,  a  tendency  which  is 
immediately  met  by  an  increased  discharge  of  glucose  from  the  liver. 
The  question  therefore  arises  a,s  to  how  the  muscles  or  other  tissues 
transmit   their   requirements  for   glucose    to   the    liver.     There    are   two 


672  METABOLISM 

possible  ways  by  which  this  could  be  done:  (1)  by  means  of  a  nervous 
reflex,  or  (2)  by  changes  in  the  composition  of  the  blood,  either  with 
regard  to  the  percentage  of  sugar  itself  or  beeause  of  the  appearance  in 
it  of  decomposition  products  of  glucose  or  of  some  special  exciting 
agent  or  hormone. 

In  order  to  ascertain  the  relative  importance  of  these  methods  of 
correlation  between  the  places  of  supply  and  demand  of  glucose  in  the 
normal  animal,  it  is  necessary  to  investigate  the  conditions  under  which 
an  excessive  discharge  of  glucose  occurs  as  a  result  of  overstimulation 
of  the  nervous  control,  or  because  of  the  presence  of  exciting  substances 
(hormones)  in  the  blood.  The  glycogenic  function  can  be  excited  through 
the  nervous  system  in  a  variety  of  ways  so  as  to  produce  hyperglycemia 
and  glycosuria.  This  constitutes  one  form  of  experimental  diabetes.  In 
laboratory  animals  mechanical  irritation  of  the  medulla  oblongata  and 
stimulation  of  the  great  splanchnic  nerves  act  in  this  way.  Similar  stimula- 
tion may  also  occur  under  certain  conditions  in  man.  Excitation  as  a  result 
of  changes  in  the  composition  of  the  blood  can  be  produced  experimen- 
tally by  certain  drugs  (phlorhizin),  or  by  the  removal  of  certain  of  the 
ductless  glands  or  the  injection  of  extracts  prepared  from  them,  such 
as  epinephrine. 

Nerve  Control  and  the  Nervous  Forms  of  Experimental  Diabetes. — 

The  simplest  experimental  condition  which  illustrates  the  relationship 
between  the  nervous  system  and  the  blood  sugar  is  electrical  stimulation 
of  the  great  splanchnic,  nerve  in  animals  in  which,  by  previous  feeding 
with  carbohydrates,  a  large  amount  of  glycogen  has  been  deposited  in 
the  liver.  By  examination  of  the  blood  as  it  is  discharged  into  the  vena 
cava  from  the  hepatic  veins,  the  increase  in  blood  sugar  is  very  evident 
in  from  five  to  ten  minutes  after  the  first  application  of  the  stimulus; 
but  it  is  not  until  later  that  a  general  hyperglycemia  becomes  estab- 
lished. The  conclusion  which  we  may  draw  from  these  results  is  that 
the  splanchnic  nerve  contains  efferent  fibers  controlling  the  rate  at 
which  glycogen  becomes  converted  to  glucose  in  the  liver.  The  center 
from  which  these  fibers  originate  is  situated  somewhere  in  the  medulla 
oblongata,  for  the  irritation  that  is  set  up  by  puncturing  this  portion  of 
the  nervous  system  with  a  needle  yields  results  similar  to  those  which 
follow  splanchnic  stimulation.  This  "glycogenic"  or  diabetic  center,  as 
it  has  been  called,  must  be  provided  with  afferent  impulses.  Such  im- 
pulses have  indeed  been  described  in  the  vagus  nerves,  but  their  dem- 
onstration is  by  no  means  an  easy  matter  on  account  of  the  disturbance 
in  the  respiratory  movements  coincidently  produced  by  the  stimulation. 
The  changes  that  such  disturbances  bring  about  in  the  aeration  of  the 


THE    METABOLISM    OP   THE    CARBOHYDRATES  673 

blood  may  in  themselves  be  responsible  for  the  hyperglycemia  (see  page 
332).  1 1  ean  at  least  be  said  that  when  the  respiratory  disturbances  are 
guarded  against,  as  by  intratracheal  insufflation  of  oxygen,  vagal  hyper- 
glycemia  is  much  less  marked,  if  not  entirely  absent.  But  this  question 
awaits  more  thorough  investigation. 

The  increased  glycogenolysis  which  results  from  stimulation  of  the 
efferent  fibers  in  the  splanchnic  nerves  may  depend  either  on  a  direct 
control  exercised  over  the  glycogenic  functions  of  the  hepatic  cells,  or 
on  the  discharge  into  the  blood  of  some  hormone  which  excites  the 
glycogenolytic  process.  It  must  furthermore  not  be  lost  sight  of  that 
the  glycogenolysis  may  be  secondary  to  local  asphyxial  conditions  in 
the  liver  cells  resulting  from  vasoconstriction.  From  their  anatomic 
position,  the  adrenals  are  to  be  thought  of  as  the  source  of  the  hormone, 
and  evidence  that  splanchnic  hyperglycemia,  is  due  to  hypersecretion 
from  these  glands  has  seemed  to  be  furnished  by  the  fact  that  after  they 
are  extirpated  splanchnic  stimulation  no  longer  produces  hyperglycemia, 
neither,  indeed,  does  puncture  of  the  medulla.  There  is  also  no  doubt 
that  the  nervous  system,  acting  by  way  of  the  splanchnic  nerves,  does 
exercise  a  control  over  the  discharge  of  the  internal  secretion  of  the 
adrenal  glands  and  that  extracts  of  the  gland,  which  we  must  suppose 
act  in  the  same  way  as  the  internal  secretion,  cause  hyperglycemia  when 
injected  intravenously   (epinephine  hyperglycemia   and   glycosuria). 

But  on  theoretical  grounds  alone,  certain  difficulties  immediately  pre- 
sent themselves  in  accepting  this  as  the  mechanism  by  which  the  nervous 
system  controls  the  sugar  output  of  the  liver,  for  if  increased  sugar 
formation  in  the  liver  is  dependent  on  a  discharge  of  epinephrine,  the 
question  may  be  asked  why  this  secretion  should  be  caused  to  traverse 
the  entire  circulation  before  reaching  the  liver. 

There  are,  besides,  certain  experimental  facts  which  do  not  conform 
with  such  a  view.  Thus,  after  complete  severance  of  the  hepatic  plexus 
of  nerves,  stimulation  of  the  splanchnic  nerve  does  not  cause  the  usual 
degree  of  hyperglycemia,  whereas  electric  stimulation  of  the  peripheral 
end  of  the  cut  plexus  does  cause  it.  On  the  one  hand,  therefore,  there 
is  evidence  that  stimulation  of  the  efferent  nerve  path  above  the  level  of 
the  adrenals  has  no  effect  on  the  sugar  production  of  the  liver  in  the 
absence  of  these  glands;  and  on  the  other,  we  see  that  when  they  are 
present,  stimulation  of  the  nerve  supply  of  the  liver  is  effective,  even 
though  the  point  of  stimulation  is  beyond  them.  There  is  but  one  con- 
clusion that  we  may  draw — namely,  that  the  functional  integrity  of  the 
efferent  nerve-fibers  that  control  the  glycogenolytic  process  of  the  liver 
depends  on  the  presence  of  the  adrenals,  very  probably  because  of  the 
hormone  which  the  glands  secrete  into  the  blood.     This  conclusion  is 


674  1MKTAB0LISM 

corroborated  by  the  fact  that  stimulation  of  the  hepatic  plexus,  even 
■with  a  strong  electric  current,  some  time  after  complete  removal  of 
both  adrenals,  is  not  followed  by  the  usual  degree  of  excitement  of  the 
glycogenolytic  process. 

These  experiments  demonstrate  an  important  relationship  between 
the  nervous  control,  and  at  least  one  form  of  hormone  control,  of  the 
sugar  output  of  the  liver.  They  indicate  that  when  a  sudden  increase 
of  blood  sugar  is  required,  the  glycogenic  center  sends  out  impulses 
which  not  only  directly  excite  the  breakdown  of  glycogen  in  the  he- 
patic cells,  but  also  simultaneously  influence  the  adrenals  in  such  a  man- 
ner as  to  produce  more  epinephrine  in  the  blood  and  so  augment  the  ac- 
tion of  the  nerve  impulse. 

We  are  as  yet  quite  in  the  dark  as  to  the  mechanism  by  which  the 
nerve  impulses  or  the  hormone  brings  about  increased  glycogenolysis. 
It  must  consist  of  a  removal  of  the  influence  that  prevents  glycogenolysis 
from  occurring  in  the  normal  liver,  for  it  has  been  shown  by  direct  ob- 
servation that  there  is  no  increase  in  the  amount  of  glycogenase  present 
in  extracts  of  the  liver  removed  from  diabetic  animals  over  that  present 
in  extracts  of  the  liver  of  normal  animals.  The  possible  nature  of  this 
influence  has  already  been  discussed  (page  669).  The  change  may  con- 
sist either  in  a  loosening  of  the  combination  between  the  glycogen  and 
the  protoplasm  of  the  liver  cell,  or  in  a  removal  of  the  chemical  influence 
that  ordinarily  prevents  the  glycogenase  from  attacking  the  glycogen. 
In  the  former  case  the  glycogen  liberated  from  its  union  with  the  sus- 
tentacular  substances  would  either  become  attacked  by  the  glycogenase 
present  in  the  liver  cell  itself  or  it  would  first  of  all  migrate,  as  glyco- 
gen, into  the  blood  capillaries  and  there  be  attacked  by  the  blood 
glycogenase.  Evidence  for  the  possibility  of  the  occurrence  of  such  a 
process  has  already  been  given  (page  670).  The  chemical  change  re- 
ferred to  under  the  second  possibility  might  consist  in  an  alteration  in 
the  hydrogen-ion  concentration  of  the  liver  cell,  a  change,  however, 
which  for  obvious  reasons  it  is  impossible  to  investigate. 

Nervous  Diabetes  in  Man. — The  main  interest  attaching  to  the  inves- 
tigation of  these  nervous  forms  of  experimental  diabetes  depends  on  the 
insight  which  they  afford  us  into  the  nature  of  the  mechanism  by  which 
a  prompt  mobilization  of  glucose  may  be  brought  about  in  the  normal 
animal.  There  is  also  some  evidence  that  a  relationship  may  exist  be- 
tween certain  of  the  clinical  varieties  of  the  disease  in  man  and  repeated 
excitation  of  glycogenolysis  brought  about  by  nerve  stimulation.  In- 
creased glucose  output  from  the  liver  as  a  result  of  nerve  excitation 
may  be  a  normal  process,  but  there  is  reason  to  believe  that  frequent 
repetition  of  this  process  tends  to  induce  a  permanent  rise  in  the  glucose 


THE    METABOLISM    OF   THE   CARBOHYDRATES  675 

level  of  the  blond  and  therefore  a  tendency  to  diabetes.  There  have 
recently  been  collected  several  facts  which  lend  some  support  to  this 
view.  The  frequent  occurrence  of  diabetes  in  those  predisposed  by 
inheritance  to  neurotic  conditions,  or  in  those  whose  daily  habits  entail 
much  nerve  strain,  and  the  aggravation  of  the  symptoms  which  is  likely 
to  follow  when  a  diabetic  patient  experiences  some  nervous  shock,  all 
point  in  this  direction. 

Diabetes  is  common  in  locomotive  engineers  and  in  the  captains  of 
ocean  liners — that  is,  in  men  who  in  the  performance  of  their  daily  duties 
are  frequently  put  under  a  severe  nerve  strain.  It  is  apparently  in- 
creasing- in  men  engaged  in  occupations  that  demand  mental  concentra- 
tion and  strain,  such  as  in  professional  and  business  work.  Cannon23 
found  glycosuria  in  four  out  of  nine  students  after  a  severe  examination, 
but  only  in  one  of  them  after  an  easier  examination.*  In  the  urine  of 
twenty-four  members  of  a  famous  football  squad,  sugar  was  found  pres- 
ent in  twelve  immediately  after  a  keenly  contested  game.  Anxiety  and 
excitement  were  responsible  for  its  appearance,  for  five  of  the  twelve 
were  substitutes  who  did  not  get  into  the  game. 

Although  these  nervous  conditions,  by  excitement  of  hepatic  glyco- 
genosis, produce  at  first  nothing  more  than  an  excessive  discharge  of 
sugar  into  the  blood — a  condition  which  is  exactly  duplicated  in  our 
laboratory  experiments  by  stimulation  of  the  nerve  supply  of  the  liver — 
their  repetition  may  gradually  lead  to  the  development  of  a  permanent 
form  of  hyperglycemia.  To  prevent  the  repetition  of  these  transient 
hyperglycemias  must  be  one  of  our  aims  in  the  treatment  of  early  stages 
of  the  disease. 

Although  there  can  he  no  doubt  that  the  glycogenic  function  of  the 
liver  is  subject  to  nerve  control,  it  is  probable  that  its  control  by  hor- 
mones is  of  equal  if  not  greater  importance.  This  dual  control  of  a 
glandular  mechanism  is  by  no  means  unique  for  the  glycogenic  function, 
for  we  have  already  seen  it  to  exist  in  the  case  of  the  gastric  glands 
and  the  pancreas,  and  it  is  probable  that  it  also  exists  in  the  case  of 
the  thyroid.  It  may  well  be  that  the  nerve  control  of  the  glycogenic 
function  has  to  do  only  with  those  transitory  changes  in  sugar  produc- 
tion that  would  be  demanded  by  sudden  activities  of  muscle,  and  that 
the  hormone  control  has  to  do  with  the  more  permanent  process  of  build- 
ing up  and  breaking  down  of  glycogen  to  meet  the  general  metabolic 
requirements  of  the  tissues. 


"We   have    been    unable    to    confirm    this    observation    even    though    the    examinations    were    made 
unusually   "nerve-racking." 


676  METABOLISM 

HORMONE  CONTROL  AND  PERMANENT  DIABETES 

Nervous  excitation  can  explain  only  transitory  increases  in  blood  sugar, 
the  more  permanent  hyperglycemias  being  dependent  upon  some  dis- 
turbance in  the  hormone  control  of  carbohydrate  utilization.  This  dis- 
turbance is  a  much  more  serious  affair  than  that  produced  by  nervous 
excitation.  In  the  latter  case  the  hyperglycemia  ceases  whenever  all 
of  the  glycogen  stores  of  the  liver  have  been  exhausted;  whereas  a  dis- 
turbance in  the  hormone  control,  besides  causing  as  its  first  step  a 
breakdown  of  all  the  available  glycogen,  goes  on  to  cause  a  production 
of  sugar  out  of  protein.  A  process  of  gluconeogenesis  (new  formation 
of  glucose)  becomes  superadded  on  one  of  glycogenolysis. 

To  ascertain  the  nature  of  this  hormone  and  the  mechanism  of  its 
action  has  been  the  object  of  most  of  the  researches  on  those  forms  of 
diabetes  produced  by  changes  in  certain  of  the  ductless  glands.  The 
following  possibilities  may  be  considered:  (1)  that  it  is  the  concentration 
of  glucose  in  the  blood:  (2)  that  it  is  the  presence  in  the  blood  of  decom- 
position products  of  glucose:  (3)  that  it  is  due  to  a  hormone  produced 
from  some  ductless  gland.  Regarding  the  first  of  these  possibilities,  it 
is  supposed  that  the  mechanism  involved  in  the  adjustment  between  the 
blood  sugar  and  the  glycogenic  function  is  one  explicable  on  the  basis 
of  the  law  of  mass  action ;  namely,  that  glycogen  becomes  converted 
into  glucose  whenever  the  blood  flowing  to  the  liver  contains  less  than 
its  normal  concentration  of  glucose,  and  conversely,  when  this  blood 
contains  an  excess  of  glucose,  as  during  absorption,  a  glycogen-building 
process  takes  place.  Although  there  can  be  little  doubt  that  the  process 
of  glycogen  formation  or  destruction  will  depend  to  a  certain  extent 
upon  the  amount  of  glucose  present  in  the  blood  flowing  to  the  liver 
cells,  yet  it  is  impossible  that  this  can  be  an  important  means  in  the 
control  that  exists  between  sugar  production  by  the  liver  and  sugar 
consumption  by  the  tissues,  because  the  sugar  that  is  added  to  the  portal 
blood  during  absorption  would  mask  any  depletion  caused  by  sugar 
consumption  in  the  tissues. 

The  second  possibility — that  the  hormone  is  some  decomposition  prod- 
uct of  glucose — would  appear  to  have  some  support,  if  we  consider  this 
hormone  to  be  an  acid  product  (carbon  dioxide  or  lactic)  produced  by 
sugar  metabolism,  for  it  is  known  that  an  increase  in  the  hydrogen-ion 
concentration  of  the  blood  flowing  to  the  liver  cells  excites  a  glycogen- 
olysis. As  we  have  already  seen,  however,  it  is  difficult  to  secure  ex- 
perimental  evidence,  in  anesthetized  animals  at  least,  that  glycogen- 
olytic activity  is  readily  excited  in  this  way. 

The  third  possibility — that  some  specific  hormone  may  exist  in  the 


THE    METABOLISM    OF    THE    CARBOHYDRATES  G77 

blood  exciting  the  glycogenolytic  process— is  investigated  by  producing 
disturbances  involving  various  of  the  ductless  glands,  particularly  the 
pancreas,  the  adrenals,  the  parathyroids  and  the  pituitary.  The  influ- 
ence of  certain  of  these  glands  may  be  closely  bound  up  with  that 
exercised  through  the  nervous  control,  as  we  have  seen  to  be  the  case 
with  the  adrenal  gland.  Whether  it  is  by  the  production  of  hormones 
directly  accessary  for  proper  carbohydrate  metabolism,  or  by  the  re- 
moval from  the  blood  of  such  substances  as  interfere  with  this  process, 
that  the  ductless  glands  functionate,  is  one  of  the  main  problems  we 
have  to  consider. 

Utilization  of  Glucose  in  Tissues. — Although  the  experimental  diabetes 
induced  by  disturbances  in  the  function  of  the  ductless  glands  is  at 
first  dependent  on  an  upset  of  the  glycogenic  function  and  later  of  glu- 
coneogenesis,  the  utilization  of  glucose  in  the  tissues  ultimately  becomes 
interfered  with.  It  is  therefore  important  that  we  should  digress  for  a 
moment  to  consider  briefly  what  is  known  regarding  the  process  by 
which  sugar  becomes  utilized  in  the  organism.  That  glucose  becomes 
used  up  by  active  muscle  there  can  be  no  doubt.  Thus,  if  the  muscles 
of  one  leg  in  the  frog  are  tet'anized,  the  glycogen  content,  compared  with 
that  of  the  other  leg,  will  be  found  to  be  diminished. 

At  first  sight  it  might  appear  that  the  easiest  way  to  study  the  utiliza- 
tion of  glucose  in  the  muscles  would  be  to  compare  its  concentrations 
in  the  blood  flowing  to  and  coming  from  the  muscle.  The  muscle  that 
has  been  most  successfully  employed  in  studies  of  this  kind  has  been  the 
heart.  Some  years  ago  Starling  and  Knowlton24  examined  the  consump- 
tion of  sugar  by  the  excised  mammalian  heart,  ana  in  their  earlier 
experiments  seemed  to  be  able  to  show  that  the  extent  to  -which  this 
consumption  occurred  was  4  milligrams  per  100  grams  heart  muscle 
per  hour.  A  more  thorough  repetition  of  these  experiments  later  by  Pat- 
terson and  Starling25  showed,  however,  that  the  results  can  furnish  no 
criterion  of  the  actual  consumption  of  glucose  by  the  tissue  on  account 
of  the  fact  that  the  tissue  itself  may  store  away  large  quantities  of 
carbohydrate  in  an  unused  state — i.  e.,  as  glycogen. 

Other  investigators  have  thought  to  study  the  utilization  of  glucose 
by  observing  the  rate  at  which  it  disappears  from  drawn  blood  kept  in 
a  sterile  condition  at  body  temperature  for  some  hours  after  death. 
This  process  is  called  glycolysis,  and  it  has  been  assumed  that  the  process 
is  similar  to  that  which  occurs  in  the  tissues  themselves — an  assumption, 
however,  for  which  there  is  no  warranty.  Indeed,  it  may  readily  be 
shown  that  the  glycolysis  occurring  in  blood  has  very  little  if  anything 
to  do  with  the  utilization  of  sugar  in  the  tissues,  for  it  has  been  found 
that   glucose   disappears   from   drawn  blood  very   slowly   indeed  when 


678  METABOLISM 

compared  with  the  rate  at  which  it  disappears  from  the  blood  of  animals 
in  which  the  addition  of  glucose  from  the  liver  has  been  prevented  by 
removal  of  this  viscus  (Macleod).20 

A  third  method  for  studying  the  utilization  of  glucose  consists  in 
observing  the  respiratory  exchange  of  animals.  In  normal  animals  the 
injection  of  glucose  causes  an  increase  in  the  carbon-dioxide  excretion 
and  a  rise  in  the  respiratory  quotient,  which  it  "will  be  remembered  is 
a  ratio  expressing  the  relationship  between  the  amount  of  carbon  dioxide 
excreted  and  of  the  oxygen  retained  in  the  organism.  When  carbohy- 
drate is  undergoing  combustion,  the  quotient  is  nearly  1,  whereas  with 
that  of  protein  it  is  about  0.7  (see  page  547).  By  observing  the  quotient 
under  given  conditions  one  can  compute  the  proportions  of  carbohydrate 
and  of  fat  and  protein  that  are  undergoing  metabolism.  In  the  hands 
of  Murlin  and  others,27  this  method  has  proved  of  some  value  in  settling 
certain  questions  concerning  the  utilization  of  glucose  in  normal  and 
diabetic  animals ;  but  the  results  must  be  interpreted  with  great  care  on 
account  of  the  fact  that  temporary  changes  in  the  blood  may  cause  a 
greater  or  a  less  expulsion  of  carbon  dioxide  from  it.  Thus,  if  acids 
appear  in  the  blood,  they  will  dislodge  carbon  dioxide  from  it,  and 
apparently  cause  the  respiratory  quotient  to  rise.  Alkalies,  on  the  other 
hand,  apparently  cause  it  temporarily  to  fall,  and  unless  the  observa- 
tions are  done  over  a  long  period  of  time  and  with  great  care,  faulty 
conclusions  are  very  apt  to  be  drawn  from  the  results. 

Diabetes  and  the  Ductless  Glands 

We  are  now  in  a  position  to  consider  the  forms  of  experimental  dia- 
betes produced  by  disturbances  in  the  ductless  glands. 

Relationship  of  the  Pancreas  to  Sugar  Metabolism. — In  no  other  of 
the  many  causes  of  diabetes  has  greater  interest  been  shown  than  in 
that  due  to  disturbance  in  the  pancreatic  function.  Many  of  the  earlier 
clinicians  that  followed  cases  of  diabetes  mellitus  into  the  postmortem 
room,  noted  that  definite  morbid  changes  in  the  pancreas  were  a  fre- 
quent "accompaniment  of  the  disease.  Prompted  by  these  observations, 
several  investigators  attempted  experimental  extirpation  of  the  gland, 
but  did  not  succeed  in  producing  glycosuria  in  the  few  animals  that 
survived  the  operation.  Their  failure,  no  doubt,  resulted  from  incom- 
plete extirpation.  To  reduce  the  severity  of  the  operation,  Claude  Ber- 
nard injected  oil  into  the  pancreatic  duct,  and  tied  it;  but  he  succeeded 
in  keeping  only  two  dogs  alive  for  any  length  of  time,  and  these  did 
not  exhibit  glycosuria.  Neither  were  other  investigators  that  adopted 
similar  methods  any  more  successful.  It  looked  as  if  the  pancreas  had 
very  little  to  do  with  the  cause  of  diabetes.    In  the  year  1889  Minkowski 


THE    METABOLISM   OF   THE   CARBOHYDRATES  070 

and  von  Mering  in  Germany,  and  de  Dominicis  in  Italy,  by  thorough 
extirpation  of  the  gland,  succeeded  in  producing  in  dogs  a  marked  and 
persisted  glycosuria,  accompanied  by  many  of  the  other  symptoms  of 
diabetes.    The  firsl  two  authors  attributed  the  condition  to  removal  of 

an  internal  secretion. 

The  course  of  the  diabetes  thus  produced  is,  however,  somewhat  differ- 
ent from  thai  usually  observed  in  man.  It  is  extremely  acute  from  the 
start,  the  (J:  N  ratio  being  1:3.6  (see  page  604),  and  it  is  unaccompanied 
by  any  of  the  classical  symptoms  seen  in  the  clinical  condition.  Experi- 
mental pancreatic  diabetes  can,  however,  be  made  to  simulate  very  closely 
the  disease  in  man.  This  was  first  of  all  demonstrated  by  Sandemeyer, 
who  found  that  if  the  greater  part  of  the  pancreas  was  removed,  the 
animals  for  some  months,  if  at  all,  were  only  occasionally  glycosurie, 
but  later  became  more  and  more  frequently  so,  until  at  last  the  condition 
typical  of  complete  pancreatectomy  supervened.  Similar  results  have 
more  recently  been  obtained  by  Thiroloix  and  Jacob,  in  France,  and  by 
Allen  in  this  country.  These  investigators  point  out  that  different  re- 
sults are  to  be  expected  according  to  whether  the  portion  of  pancreas 
which  is  left  does,  or  does  not,  remain  in  connection  with  the  duodenal 
duct.  When  this  duct  is  ligated,  atrophy  of  any  remnant  of  pancreas 
that  is  left  is  bound  to  occur,  and  this  is  associated  with  rapid  emacia- 
tion of  the  animal,  diabetes  and  death.  When  the  remnant  surrounds  a 
still  patent  duct,  a  condition  much  more  closely  simulating  diabetes  in 
man  is  likely  to  become  developed — one,  namely,  in  which  there  is,  for 
some  months  following  the  operation,  a  more  or  less  mild  diabetes, 
which,  however,  usually  passes  later  into  the  fatal  type. 

It  is,  of  course,  difficult  to  state  accurately  what  proportion  of  the 
pancreas  must  be  left  in  order  that  the  above  described  condition  may  super- 
vene. Leaving  a  remnant  amounting  to  from  one-fifth  to  one-eighth 
of  the  entire  gland  is  commonly  followed  by  a  mild  diabetes,  whereas 
if  only  one-ninth  or  less  is  left,  a  rapidly  fatal  type  develops.  As  in 
clinical  experience,  the  distinguishing  feature  between  the  mild  and  the 
severe  types  of  experimental  pancreatic  diabetes  is  the  tolerance  toward 
carbohydrates.  In  the  mild  form,  no  glycosuria  develops  unless  carbo- 
hydrate food  is  taken;  in  the  severe  form,  it  is  present  when  the  diet  is 
composed  entirely  of  flesh.  It  is  thus  shown  that  "by  removal  of  a 
suitable  proportion  of  the  pancreas,  it  is  possible  to  bring  an  animal 
to  the  verge  of  diabetes,  yet  to  know  that  the  animal  will  never  of  itself 
become  diabetic.  .  .  .  Such  animals,  therefore,  constitute  valuable 
test  objects  for  judging  the  effects  of  various  agencies  with  respect  to 
diabetes" — (Allen18).  It  therefore  becomes  theoretically  possible  to  in- 
vestigate, on  the  one  hand,  other  conditions  which  will  have  an  influence 


680  METABOLISM 

similar  to  removal  of  more  of  the  gland,  or,  on  the  other,  conditions 
which  might  prevent  the  incidence  of  diabetes,  even  though  this  extra 
portion  of  pancreas  is  removed. 

From  the  work  which  he  has  already  done,  Allen  believes  that  he  has 
sufficient  evidence  to  show  that  the  continued  feeding  with  excess  of 
carbohydrate  food  will  surely  convert  a  mild  into  a  severe  case,  and  in 
one  experiment  he  succeeded  in  bringing  about  the  same  transition  by 
performing  puncture  of  the  medulla — that  is,  by  creating  an  irritative 
nervous  lesion.  By  none  of  the  other  means  usually  employed  to  produce 
experimental  glycosuria  could  the  bordering  case  be  made  diabetic, 
although  one  such  animal  became  acutely  diabetic  after  ligature  of  the 
portal  vein.  To  the  clinical  worker  the  value  of  these  results  lies  in  the 
fact  that  they  furnish  experimental  proof  that  a  so-called  latent  case 
of  diabetes — that  is,  one  that  has  a  Ioav  tolerance  value  for  carbohy- 
drates— may  be  prevented  from  developing  into  a  severe  case  by  proper 
control  of  the  diet.  Attempts  to  show  whether  or  not  there  are  any 
conditions  which  might  bring  about  improvements  in  animals  that  were 
just  diabetic  have  not  as  yet  been  sufficiently  made  to  warrant  any  con- 
clusions that  could  help  us  in  the  treatment  of  human  cases.  The  en- 
couragement of  the  internal  pancreatic  secretion  by  diminution  of  that 
discharge  into  the  intestine  may  be  of  value. 

The  certainty  with  which  diabetes  results  from  pancreatectomy  in  dogs, 
as  well  as  the  frequent  occurrence  of  demonstrable  lesions  in  the  pan- 
creas in  diabetes  in  man.  leaves  no  doubt  that  this  gland  must  be  in  some 
way  essential  in  the  physiologic  breakdown  of  carbohydrates  in  the 
normal  animal,  but  how,  we  can  not  at  present  tell.  All  we  know  is 
that  the  first  change  to  occur  after  the  gland  is  removed  is  a  sweeping 
out  of  all  but  a  trace  of  the  glycogen  of  the  liver,  although  the  muscles  may 
retain  theirs;  indeed,  in  the  cardiac  muscle  there  may  be  more  than 
the  usual  amount.28  Xor  can  any  glycogen  be  stored  in  the  liver  when 
excess  of  carbohydrates  is  fed.  After  the  glycogen  has  disappeared, 
gluconeogenesis  sets  in,  so  that  the  tissues  come  to  melt  away  into  sugar, 
and  all  the  symptoms  of  acute  starvation,  associated  with  certain  others 
that  are  possibly  due  to  a  toxic  action  of  the  excess  of  sugar  or  other 
abnormal  products  in  the  blood,  make  their  appearance. 

So  far  it  might  be  permissible  to  consider  an  overproduction  of  glu- 
cose as  the  cause  of  the  hyperglycemia  of  pancreatic  diabetes,  just  as 
Ave  have  seen  it  to  be  of  these  forms  of  hyperglycemia  that  are  due  to 
stimulation  of  the  nervous  system ;  but  this  can  not  be  the  case,  for 
another  very  definite  abnormality  in  metabolism  becomes  evident — 
namely,  an  inability  of  the  tissues  to  burn  sugar.  This  fact  is  ascer- 
tained by  observing  the  respiratory  quotient.     When  glucose  is  added 


THE    METABOLISM    OF   THE   OABBOHYDBATES  681 

to  the  blood  in  the  case  of  a  completely  diabetic  animal,  no  change  oc- 
curs in  the  quotient. 

There  are,  therefore,  two  essential  disturbances  of  carbohydrate 
metabolism  in  pancreatic  diabetes — overproduction  of  sugar  and  aboli- 
tion of  the  ability  of  the  tissues  to  use  it.  It  becomes  important  for  us 
to  see  "whether  the  tissues  exhibit  this  inability  to  use  sugar  when  they 
are  isolated  from  the  animal ;  for  if  they  should,  a  much  more  searching 
investigation  of  the  essential  cause  of  their  inability  would  be  possible 
than  is  the  case  when  they  are  functioning  along  with  the  other  organs 
and  tissues.  The  earlier  experiments  of  Lepine  and  his  pupils,  which  seemed 
to  show  that  diabetic  blood  did  not  possess  the  glycolytic  power  of 
normal  blood;  and  those  of  Cohnheim,  from  which  it  was  concluded  that 
mixtures  of  the  expressed  juices  of  muscle  (liver)  and  pancreas,  although 
ordinarily  destroying  glucose,  failed  to  do  so  when  they  were  taken  from 
a  diabetic  animal,  are  now  known  to  be  erroneous. 

The  failure  to  show  a  depression  of  glycolytic  power  by  these  methods 
prompted  Knowlton  and  Starling24  to  investigate  the  question  whether 
any  difference  is  evident  in  the  rate  with  which  glucose  disappears  from 
a  mixture  of  blood  and  saline  solution  used  to  perfuse  a  heart  outside 
the  body,  according  to  whether  the  heart  was  from  a  normal  or  a  dia- 
betic dog.  In  the  first  series  of  observations  which  these  workers  made, 
it  was  thought  that  the  normal  heart  used  glucose  at  the  rate  of  about 
4  mg.  per  100  gm.  of  heart  substance  per  minute ;  whereas  that  of  a  dia- 
betic (depancreatized)  animal  used  less  than  1  mg.  If  such  striking 
differences  in  the  rate  of  sugar  consumption  could  make  themselves 
manifest  for  so  relatively  small  a  mass  of  muscular  tissue  as  that  of  the 
heart,  it  is  permissible  to  assume  that  a  much  more  striking  difference 
could  be  demonstrated  when  the  perfusion  fluid  is  made  to  traverse  all 
or  practically  all  of  the  skeletal  muscles,  as  well  as  the  heart.  For  this 
purpose  an  eviscerated  animal  may  be  employed — that  is,  one  in  which 
the  abdominal  viscera  are  removed  after  ligation  of  the  celiac  axis  and 
mesenteric  arteries,  and  the  liver  is  eliminated  by  mass  ligation  of  its 
lobes.  Using  such  preparations,  R.  G.  Pearce  and  Macleod29  found  that 
the  rate  at  which  glucose  disappears  from  the  blood,  although  very 
irregular,  is  in  no  way  different  in  completely  diabetic  as  compared 
with  normal  dogs.  They  were  thus  unable  to  confirm  any  of  Knowlton 
and  Starling's  earlier  conclusions.  Patterson  and  Starling  subsequently 
pointed  out  that  a  serious  error  was  involved  in  the  earlier  perfusion 
experiments,  partly  on  account  of  a  remarkable  but  irregular  disap- 
pearance of  -glucose  from  the  lungs,  and  partly  because  the  diabetic 
heart  may  contain  a  considerable  excess  of  glycogen,  from  which  its 


682  METABOLISM 

demands  for  sugar  may  be  met  without  calling  on  that  of  the  perfusion 
fluid. 

In  spite  of  the  failure  to  show  that  the  isolated  tissues  of  diabetic 
animals  have  a  lower  glucose-consuming  power  than  those  of  normal 
animals,  it  is  important  from  a  practical  standpoint  that  we  should 
know  something  regarding  tlic  possible  nature  of  the  disturbance  which 
a  removal  of  the  pancreas  entails.  Even  if  we  could  not  tell  exactly 
hoAv  this  disturbance  operates,  it  would  be  of  value  to  know  whether 
it  depends  on  the  removal  from  the  organism  of  some  hormone  that  is 
essential  to  carbohydrate  utilization,  for,  if  this  were  proved  to  be  the 
case,  encouragement  would  be  offered  to  seek  for  the  chemical  nature 
of  this  hormone  so  that  we  might  administer  it  with  the  object  of  re- 
moving the  diabetic  state.  The  hope  of  a  fruitful  outcome  of  such  an 
investigation  is  encouraged  by  the  success  of  researches  on  diseases  of 
other  ductless  glands,  particularly  the  thyroid. 

The  removal  of  some  hormone  necessary  for  proper  sugar  metab- 
olism is,  however,  by  no  means  the  only  way  by  which  the  results  can 
be  explained,  for  we  can  assume  that  the  pancreas  owes  its  influence 
over  sugar  metabolism  to  some  change  occurring  in  the  composition  of 
the  blood  as  this  circulates  through  the  gland — a  change  which  is  de- 
pendent on  the  integrity  of  the  gland  and  not  on  any  one  enzyme  or 
hormone  which  it  produces.  It  is  obvious  that  the  results  of  removal 
of  the  gland  could  be  explained  in  terms  of  either  view,  and  indeed 
there  is  but  one  experiment  which  would  permit  us  to  decide  which  of 
them  is  correct.  This  consists  in  seeing  whether  the  symptoms  which 
follow  pancreatectomy  are  removed,  and  a  normal  condition  reestab- 
lished, when  means  arc  taken  to  supply  the  supposed  missing  internal 
secretion  to  the  organism;  if  they  should  be,  conclusive  evidence  would 
be  furnished  that  it  is  by  "internal  secretion"  and  not  by  "local  in- 
fluence" that  the  gland  functionates. 

The  experiments  have  been  of  two  types:  in  the  one,  variously  pre- 
pared extracts  of  the  glands  have  been  employed,  and  in  the  other, 
blood  which  is  presumably  rich  in  the  internal  secretion.  The  most 
recent  work  with  pancreatic  extracts  has  shown  that  injection  of  pan- 
creatic extracts  into  a  depancreatized  animal  produces  no  change  in  the 
respiratory  quotient,  although  injections  of  extracts  of  pancreas  and 
duodenum  may  produce  a  temporary  fall  in  the  dextrose  excretion  in 
the  urine  on  account  of  the  alkalinity  of  the  extract.  Neither  have 
experiments  with  blood  transfusions  yielded  results  that  are  any  more 
satisfactory.  In  undertaking  these  experiments  it  is  of  course  assumed 
that  the  internal  secretion  is  present  in  the  blood,  and  that  if  this  blood 
is  supplied  to  an  animal  suffering  from  diabetes  because  of  the  loss  of 


THE    METABOLISM    OF   THE   CARBOHYDRATES  (is:! 

its  pancreas,  it  will  restore  il  to  a  aondiabetic  state.  The  general  eon- 
elusion  thai  may  be  drawn  from  the  numerous  researches  of  this  nature, 
is  thai  there  is  no  evidence  thai  the  blood  of  a  normal  animal,  oven 
when  it  is  from  the  pancreatic  vein,  contains  an  internal  secretion  that 
can  restore  to  a  diabetic  animal  any  of  its  lost  power  to  utilize  carbo- 
hydrates. "When  the  extent  of  glycosuria  alone  is  used  as  the  criterion 
of  the  state1  of  carbohydrate  metabolism,  serious  errors  in  judgment  are 
liable  to  be  drawn.  The  condition  of  the  blood  sugar  and  the  extent 
and  character  of  the  respiratory  exchange  are  the  most  reliable  indexes. 

DIABETIC  ACIDOSIS  OR  KETOSIS 

Nature  and  Cause. — Much  confusion  has  existed  in  medical  literature 
over  the  correct  definition  of  acidosis,  mainly  because  the  term  "was  first 
used  for  the  particular  variety  of  the  condition  observed  in  the  later 
stages  of  diabetes  mellitus.  The  acids  which  accumulate  in  the  tissue 
fluids  in  this  disease  are  acetoacetic  and  /3-oxybutyric,  and  they  are 
oxidation  products  of  acetone,  which  is  again  derived  from  fatty  acids 
by  a  faulty  metabolism  (see  page  709).  The  essential  cause  of  the 
acidosis  is  therefore  entirely  different  from  that  in  nephritis ;  in  dia- 
betes foreign  acids  are  added  to  the  blood,  whereas  in  nephritis  the 
acids  of  a  normal  metabolism  accumulate  because  of  faulty  excretion 
through  the  kidneys.  The  usual  signs  of  acidosis  exist  in  both  cases, 
because  the  surplus  of  acid  depletes  the  store  of  bicarbonate  and 
causes  changes  in  the  alveolar  C02,  in  the  C02-absorbing  powrer  of  the 
blood,  in  the  reserve  alkalinity,  and  in  the  acid  excretion  by  the  kidney. 
It  is  important  to  recognize  the  special  nature  of  diabetic  acidosis  by  a 
separate  name — ketosis. 

The  chemical  processes  by  which  the  ketone  bodies  are  produced  is 
discussed  elsewhere  (page  709).  It  remains  for  us  to  consider  the 
general  nature  of  the  metabolic  disturbance  responsible  for  their  ap- 
pearance in  diabetes. 

For  the  thorough  combustion  of  fat  in  the  animal  body  a  certain 
amount  of  carbohydrate  must  be  simultaneously  burned.  Fat  evidently 
is  a  less  readily  oxidized  foodstuff  than  sugar;  it  needs  the  fire  of  the 
burning  sugar  to  consume  it.  If  the  carbohydrate  fires  do  not  burn 
briskly  enough,  the  fat  is  incompletely  consumed;  it  smokes,  as  it  were, 
and  the  smoke  is  represented  in  metabolism  by  the  ketones  and  derived 
acids.  Such  a  closing  down  of  the  carbohydrate  furnaces  may  be 
brought  about  either  by  curtailment  of  the  intake  of  carbohydrates,  as 
in  starvation  (page  569),  or  by  some  fault  in  the  mechanism  of  the 
furnace  itself,  as  in  diabetes.     Besides  fat,  protein  may  also  contribute 


684  METABOLISM 

to  the  production  of  ketones  when  carbohydrate  combustion  is  de- 
pressed. Fundamentally,  therefore  ketosis  in  diabetes  is  due  to  the 
same  cause  as  in  starvation — namely,  an  improper  adjustment  between 
the  metabolisms  of  fat  and  carbohydrate. 

Bearing  these  principles  in  mind,  it  is  easy  to  see  how  the  intensity 
of  acidosis  which  develops  during  starvation  will  depend  upon  the  re- 
lative metabolism  of  carbohydrate,  on  the  one  hand,  and  of  fat  and 
protein,  on  the  other;  it  will  therefore  depend  on  the  amounts  of  these 
foodstuffs  which  have  been  stored  in  the  organism,  and  this  again  will 
depend  on  the  nature  of  the  diet  previous  to  the  starvation  period.  For 
the  first  few  days  following  entire  abstinence  from  food  in  a  healthy, 
well-nourished  individual,  very  few  if  any  ketones  will  be  excreted  in 
the  urine,  because  the  carbohydrate  stored  in  the  body  as  glycogen  has 
sufficed  during  this  time  to  maintain  the  proper  proportion  between  fat 
and  carbohydrate.  Afterwards,  however,  their  appearance  is  to  be  ex- 
pected, because  the  glycogen  stores  become  exhausted  long  before  those 
of  fat.  If  starvation  is  still  further  prolonged,  a  stage  will  come  when 
the  fat,  as  well  as  the  carbohydrate,  is  used  up  so  that  the  organism  has 
now  to  subsist  on  protein  alone.  When  this  stage  arrives,  the  ketones 
will  diminish,  for,  although  they  might  be  derived  from  certain  of  the 
amino  acids,  yet  this  does  not  actually  occur,  because  a  large  part  of  the 
protein  molecule  (nearly  half)  also  becomes  changed  into  glucose,  which 
by  burning,  as  above  explained,  prevents  the  formation  of  ketones  from 
the  other  part  of  the  molecule.  For  the  same  reasons,  marked  acidosis 
Avill  not  be  expected  to  occur  during  any  stage  of  starvation  in  lean 
persons,  who  from  the  start  must  utilize  mainly  their  stored  protein  to 
supply  the  fuel  upon  which  to  live. 

In  diabetes  exactly  the  same  principles  apply,  but  to  an  organism  in 
which  the  ability  to  metabolize  carbohydrate  has  been  depressed,  so  that 
"the  maximum  rate  at  which  dextrose  can  be  oxidized  is  fixed  at  some 
level  which  is  absolutely  lower  than  in  health."30  Therefore,  since  a  cer- 
tain proportionality  must  exist  between  the  rates  of  combustion  of  fat 
and  carbohydrate,  the  diabetic  can  thoroughly  oxidize  less  fat;  in  other 
words,  an  amount  of  fat  which  could  readily  be  burned  in  a  healthy  body 
is  improperly  burned  by  the  diabetic,  and  ketones  and  their  acids  ac- 
cumulate. 

Starvation  Treatment. — "In  order  to  check  a  diabetic  acidosis,  it  is 
necessary  to  restore  the  proper  ratio  of  fatty  acid  to  glucose  oxidation," 
which  can  best  be  done  by  starvation,  rest  in  bed  and  warmth.  But  this 
treatment  may  not  at  first  suffice,  because  we  have  to  deal  not  only  with 
the  acidosis  bodies  derived  from  fat,  but  with  those  which  can  be  derived 
from  protein  on  account  of  the  diabetic  organism  having  lost  the  .power 


THE    METABOLISM    OF   THE   CARBOHYDRATES  (',<) 

even  of  burning  the  glucose  which  is  derived  from  this  foodstuff.  By 
persistence  in  the  starvation,  however,  the  ability  of  the  organism  to 
utilize  carbohydrate  usually  becomes  so  Ear  restored  thai  enough  burns  to 
prevent  acidosis.  Every  ease  of  diabetes  can  not,  therefore,  be  expected 
to  react  in  the  same  way  to  starvation,  the  determining  condition  being 
the  relation  between  the  quantities  of  glycogen  and  fat  stored  in  the  body 
at  the  outset  of  the  fasting  period.  This  relationship  depends  on  the 
nature  of  the  previous  diet. 

To  sum  up,  "fasting  will  lower  acidosis  either  in  health  or  in  diabetes, 
if  it  has  the  effect  of  stopping  a  one-sided  metabolism  and  throwing  the 
tissues  on  a  more  nearly  balanced  ration  of  fatty  acids  and  glucose" — 
(Woodyatt).  A  practical  point  may  be  noted  here — namely,  that  there 
is  likely  to  be  more  danger  of  serious  acidosis  developing  during  starva- 
tion in  fat  than  in  lean  diabetics.  The  importance  of  our  appreciation  of 
these  facts  in  the  starvation  treatment  of  diabetes  will  be  self-evident. 


CHAPTER  LXXVII 

FAT  METABOLISM 

Before  considering  the  physiology  of  fats,  a  few  of  the  most  essential 
points  regarding  their  chemistry  may  be  of  assistance. 

THE  CHEMISTRY  OF  FATTY  SUBSTANCES 

It  is  usual  to  classify  all  substances  that  are  soluble  in  ether  as  lipoids. 
They  include  fatty  acids,  neutral  fats,  cholesterols,  cholesterol  esters,  and 
phospholipins. 

The  fatty  acids  belong  to  two  main  homologous  series,  which  differ  from 
each  other  with  regard  to  whether  they  are  saturated  or  unsaturated.  A 
saturated  fatty  acid  is  typified  by  palmitic,  whose  formula  is  CH3-CH2-CH2- 
CH2-CH2-CII2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-COOH,  or"  CH3- 
(CH2)14-COOH ;  that  is  to  say  it  is  a  higher  member  of  the  series  to  which 
acetic  acid  (CH3-COOH)  belongs,  differing  from  the  latter  in  having  four- 
teen extra  methyl  radicles,  each  joined  to  its  neighbor  by  one  bond  or  satu- 
rated linking  on  either  side.  Another  member  of  this  series  is  stearic,  in 
which  there  are  sixteen  extra  CH2  groups  (CH3(CH2)1(,-COOH).  An  un- 
saturated fatty  acid  is  oleic  (CH3(CH2)7— CH29  =  CH-(CH2)7-COOH). 
Its  unsaturation  is  represented  in  the  formula  by  the  double  bond  or 
unsaturated  linking,  which  it  will  be  seen  occupies  a  position  in  the  mid- 
dle of  the  molecule,  the  other  methyl  radicles  being  linked  together  by 
single  bonds. 

The  fatty  acids  readily  combine  with  alkali  to  form  soaps;  thus, 
CH3(CH2)14-COOH  +  KOH=CH3(CH2)]4-COOK  +  H20,  the  reaction  being 

(palmitic  acid)  (soap) 

analogous  to  that  by  which  acetic  acid  forms  an  acetate  with  alkalies. 
In  place  of  being  combined  with  alkali,  the  COOH  (carboxyl)  group  of 
fatty  acids  may  combine  with  alcohols  to  form  substances  called  esters. 
Thus,  acetic  acid  and  ethyl  alcohol  form  ethyl  acetate, 
CH3COO  JH+JOHj  C2Hr=CH3COO-C2H,  +  H20.  When  the  alcohol  thus 
(acetic        (ethyl  (ethyl  acetate) 

acid)         alcohol) 
united  with  fatty  acid  is  glycerol  (glycerine),  in  which  there  are  three 

6S6 


PAT    METABOLISM  G87 

(»II  (hydroxyl)  groups,  1  bo  resulting  ester — called  triglyceride — is  neu- 
tral fat.    Tripalmitin  has  the  formula: 

nr,-ooc-c,n;„ 

I 

OF!  -OOC-C.,11,, 

I 
CH1-OOC-C18HM. 

T\y  boiling  neutral  fats  with  alkali  the  fatty  acid  radicles  are  split  off 
as  soaps,  leaving  the  glycerol.  This  process  is  called  saponification,  and 
it  may  be  effected  in  many  other  ways,  as  for  example  by  heating  with 
steam  or  by  the  action  of  special  enzymes  called  lipases,  which  are  widely 
distributed  in  plants  and  animals. 

The  natural  fats  are  usually  a  mixture  of  triglycerides,  and  their  dif- 
ferences in  properties  are  dependent  upon  the  relative  amounts  of  fatty 
acids  present.  The  three  most  important  in  animal  fats  are  tripalmitin, 
tristearin  and  triolein.  It  is  essential  in  the  study  of  fat  metabolism  that 
avc  should  know  the  most  important  methods  by  which  the  proportion  of 
fatty  acids  present  in  a  mixed  fat  is  determined.  These  methods  are  as 
follows : 

1.  The  melting  point.  Olein  is  liquid  at  0°  C. ;  palmitic  acid  melts  at 
62.6°  C. ;  and  stearic  at  69.3°  C.  The  solidity  of  animal  fats  depends  on 
the  proportion  of  olein,  palmitin  and  stearin  present.  Mutton  fat,  for  ex- 
ample, is  much  stiffer  than  pig  fat  because  it  contains  less  olein  and  more 
stearin.  The  melting  points  of  fats  from  different  parts  of  the  body  may 
also  vary. 

2.  The  acid  number  indicates  the  amount  of  free  fatty  acid  mixed  with 
the  fat,  and  is  determined  by  titrating  a  solution  of  a  weighed  quantity  of 
the  fat  in  alcohol  with  a  N/10  alcoholic  solution  of  KOH,  phenolphtha- 
lein  being  used  as  indicator. 

3.  The  saponification  value  indicates  the  total  amount  of  fatty  acid 
present,  both  that  which  is  free  and  that  combined  with  glycerol.  It  is 
determined  by  heating  a  weighed  amount  of  fat  with  an  exactly  known 
amount  of  alcoholic  KOH  (determined  by  titration  with  standard  acid). 
After  saponification  is  complete,  titration  of  the  mixture  shows  how  much 
alkali  has  been  used  to  combine  with  the  fatty  acid.  This  is  the  saponi- 
fication value. 

4.  The  ester  value  indicates  the  amount  of  fatty  acid  combined  with 
glycerol,  and  is  obtained  by  subtracting  the  acid  value  from  the  saponi- 
fication value. 

Besides  these  there  are  two  values,  known  as  the  iodine  and  the  Reichert- 
Meissl  values,  that  are  of  importance  because  they  depend  on  certain  char- 
acteristics of  the  fatty-acid  radicles. 


688  METABOLISM 

5.  The  iodine  value  indicates  the  amount  of  unsaturated  fatty  acids  pres- 
ent, or  the  number  of  double  bonds.  It  depends  on  the  fact  that  iodine, 
like  many  other  substances,  is  capable  of  directly  attaching  itself  to  the 
fatty-acid  chain  wherever  double  bonds  exist. 

6.  The  Reichert-Meissl  value  indicates  the  amount  of  volatile  soluble 
acid  present  in  the  fat.  It  is  determined  by  first  of  all  saponifying  the 
fat,  then  decomposing  the  soap  by  mixing  it  with  mineral  acid  and  dis- 
tilling the  liberated  fatty  acid,  the  distillate  being  collected  in  a  known 
amount  of  standard  alkali  and  titrated.  It  is  a  value  that  is  not  of  very 
great  use  in  physiologic  investigations,  but  it  is  so  in  connection  with 
food  chemistry.  Since  volatile  acids  are  present  in  butter,  the  Eeichert- 
Meissl  value  helps  us  to  distinguish  between  butter  and  margarine. 

Fat  is  insoluble  in  water  but  soap  is  soluble,  forming  a  colloidal  solu- 
tion which  presents  the  phenomenon  of  surface  aggregation  of  molecules. 
This  consists  in  the  concentration  of  the  soap  both  at  the  free  surface  of 
the  liquid,  where  a  skin  may  form,  and  at  the  interfaces  between  the 
soap  solution  and  any  undissolved  particles  present  in  it.  This  pellicle- 
formation  around  the  particles  prevents  them  from  running  together  so 
that  they  remain  suspended,  thus  forming  an  emulsion.  An  emulsion 
may  therefore  be  formed  either  of  neutral  fat  of  any  other  physically 
similar  substance.  When  fat  itself  is  used,  there  is  usually  enough  free 
fatty  acid  admixed  with  it  to  make  it  unnecessary  in  forming  the  emul- 
sion to  do  more  than  shake  the  fat  with  weak  sodium-carbonate  solution. 
With  other  substances  not  containing  any  free  fatty  acid,  some  soaps 
should  be  added.  To  preserve  the  emulsion  it  is  often  useful  to  add  some 
mucilage.  In  the  emulsified  state,  neutral  fats  are  much  more  readily 
attacked  by  lipases  than  when  they  are  present  in  an  unemulsified  state. 
Thus,  emulsified  fats  are  "digested"  by  the  relatively  small  amounts  of 
lipase  present  in  the  stomach,  whereas  neutral  fats  themselves  are  not  so. 

Fatty  acids  also  exist  in  nature  in  combination  not  with  the  triatoniic 
alcohol,  glycerol,  but  with  monatomie  alcohols  such  as  cholesterol.  These 
cholesterol  fats  differ  from  the  glycerol  fats  in  being  very  resistant  to- 
wards enzymes  and  microorganisms.  They  are  therefore  used  for  pro- 
tective purposes  in  the  animal  economy ;  for  example,  they  occur  in  the 
sebum,  the  secretion  of  the  sebaceous  glands,  where  they  serve  to  moisten 
the  hairs  and  skin.  They  are  also  present  in  cells,  in  which  it  is  prob- 
able they  take  an  important  part  in  forming  the  skeleton  of  the  cell. 
Cholesterol  is  absorbed  from  the  intestine ;  it  is  always  present  in  the  blood 
both  in  plasma  and  in  corpuscles ;  and  it  is  an  important  constituent  of  bile, 
from  which  it  may  separate  out  in  the  bile  passages  and  form  calculi 
(gallstones). 

In  the  cells  themselves  the  lipoids  are  represented  mainly  by  compounds 


FAT    METABOLISM  689 

of  a  Bomewhal  more  complex  structure— namely,  the  phospholipid.  As 
their  name  indicates,  these  consisl  chemically  of  phosphoric  acid  combined 
with  neutral  fat  and  with  a  nitrogenous  base,  cholin.  The  hest  known  of 
the  phospholipid  is  lecithin,  which  is  widely  distributed  in  the  animal  body 
(present  in  blood  and  bile  as  well  as  in  all  cells).  Other  phospholipid 
present  in  nervous  tissue  are  eephalin,  euorin  and  sphingomyelin.  There 
are  various  lecithins  distinguished  from  one  another  by  the  fatty-acid 
radicles  which  they  contain.  Distearyl-lecithin,  for  example,  has  the 
formula: 

CH2-0-OC(CH.,)11-CH3 

I 
CH  -0-OC(CH2),4-CH3 
(stearic  acid) 
CH,  -  O  O 

\    / 

(glycerol)        P 

/    \ 

OK  OCH2-CH2-N(CH,)2 

(phosphoric 

acid)  OH 

(choline) 

This  complex  molecule  can  readily  be  split  up  by  hydrolysis  (warming 
with  baryta  water)  into: 

glvcero-phosphoric  acid.  CH,  -  OH 
I   " 
CH  -OH 


CH,  -  O  O 

'       \   // 

P  ;  choline,  X 

/   \ 

OH  OH 

hydroxide) ;    and  fatty   acids. 


C2H4OH 

(CH3)3  (oxy-ethyl-ammonium 
OH 


With  hydrochloric  acid,  choline  forms  a  salt  •which  readily  forms  a 
double  salt  with  platinic  chloride.  Since  this  double  salt  forms  charac- 
teristic crystals,  it  is  used  to  identify  and  separate  lecithins.  For  quan- 
titative purposes,  however,  it  is  more  suitable  to  determine  lecithin  in- 
directly by  the  amount  of  phosphoric  acid  present  in  an  ethereal  ex- 
tract of  the  organ  or  tissue. 

Evidence  is  constantly  accumulating  to  show  that  lecithin  is  an  ex- 
tremely important  constituent  of  cells;  indeed,  it  seems  to  be  the  inter- 
mediate stage  in  the  utilization  of  neutral  fats  by  protoplasm.  Its  phos- 
phorus also  probably  serves  as  the  source  of  this  element  for  the  con- 
struction of  nucleic  acid  (see  page  637).  In  nervous  tissues  it  is  often 
associated  with  carbohydrate  molecules  (galactose),  forming  the  sub- 
stance known  as  cerebrin.  It  may  therefore  have  some  role  to  play  in 
carbohvdrate  metabolism.     Some  workers  also  attribute  to  lecithin  an 


690  M  ETABOUSM 

important  function  in  the  transference  of  substances  through  cell  mem- 
branes. When  mixed  with  water  it  swells  up  by  imbibition,  and  if  crys- 
talloids or  other  substances  are  dissolved  in  the  water,  a  means  is  offered 
for  bringing  water-soluble  and  fat-soluble  substances  into  intimate  con- 
tact. 

DIGESTION  OF  FATS 

A  certain  amount  of  fat,  especially  when  it  is  in  an  emulsified  condi- 
tion, can  be  digested  in  the  stomach  by  the  lipase  contained  in  the  gas- 
tric juice.  Most  of  it,  however,  is  digested  in  the  small  intestine,  into 
which  as  we  have  seen,  it  is  gradually  discharged  suspended  in  the  chyme. 
For  this  intestinal  digestion  of  fat  both  pancreatic  juice  and  bile  are  nec- 
essary. This  is  easily  shown  in  the  rabbit,  in  which  the  pancreatic  duet 
enters  the  intestine  at  a  considerable  distance  below  the  bile  duct.  If  the 
mesentery  is  inspected  during  the  absorption  of  fatty  food,  no  fat  in- 
jection of  the  lymphatics  will  be  noted  between  the  bile  and  the  pan- 
creatic ducts  but  only  below  the  latter.  In  the  dog,  in  which  both  the  bile 
and  the  main  pancreatic  ducts  enter  the  intestine  at  about  the  same  level, 
fat  injection  of  the  lymphatics  starts  at  this  point,  but  if  the  bile  duct 
(or  rather  the  gall  bladder)  is  transplanted  at  some  distance  down  the 
intestine,  it  will  be  found  that  the  injection  of  the  lymphatics  with  fat 
occurs  only  below  the  new  point  of  insertion  of  the  bile  duct. 

Removal  of  the  pancreas  interferes  very  materially  with  the  absorption 
of  fat.  In  man,  for  example,  absence  of  the  pancreatic  juice  alone  di- 
minishes the  absorption  of  fat  by  50  or  60  per  cent,  If  the  bile  is  also 
absent,  the  diminution  amounts  to  80  or  90  per  cent,  and  in  such  cases, 
as  is  well  known,  the  administration  of  bile  or  pancreas  powder  greatly 
improves  fat  absorption.  In  the  dog,  although  ligation  of  the  pancreatic 
duct  apparently  only  slightly  influences  fat  absorption,  removal  of  the 
pancreas  itself  greatly  interferes  with  the  process ;  from  which  fact  some 
observers  have  concluded  that  the  pancreas,  in  addition  to  its  external 
secretion  into  the  intestine,  must  produce  an  internal  secretion  into  the 
blood  which  has  something  to  do  with  the  efficient  absorption  of  the 
fat  (Pratt,  McClure  and  Vincent'48).  It  is,  however,  improbable  that  such  an 
hypothesis  is  necessary,  for  it  is  very  likely  that  the  moribund  condi- 
tion into  which  an  animal  is  brought  by  extirpation  of  the  pancreas, 
adequately  accounts  for  the  suppression  of  the  fat-absorbing  function. 

As  to  the  relative  roles  of  pancreatic  juice  and  bile  in  the  digestion  of 
fat,  we  know  of  course  that  in  the  pancreatic  juice  there  exists  a  lipolytic 
enzyme,  lipase,  which,  under  suitable  conditions  has  the  power  of  split- 
ting neutral  fat  into  fatty  acids  and  glycerine.  If  bile  is  examined,  no 
lipolytic  enzyme  will  be  found  in  it.     It  is  entirely  inactive  on  fat,  but 


PAT    METABOLISM  691 

if  we  mix  bile  with  fresh  pancreatic  juice,  which  by  itself  only  slowly 
digests  fat,  we  shall  find  that  the  bile  very  materially  increases  the  lipo- 
lytic activity  of  the  pancreatic  juice.  It  has  been  found  that  the  salts 
of  cholalic  acid,  the  so-called  bile  salts,  are  the  constituents  of  bile 
that  are  responsible  for  this  activation  of  lipase,  this  fact  having  been 
demonstrated  with  bile  salts  prepared  in  such  a  way  that  there  was  no 
possible  chance  of  any  other  biliary  constituent  being  present  as  an 
impurity.  It  is  important  to  remember,  however,  that  lipase  itself  be- 
comes slowly  activated  on  standing,  which  explains  why  it  should  be 
that  bile  added  to  pancreatic  juice  that  has  stood  Eor  some  time,  has  a 
less  evident  activating  influence  than  bile  added  to  fresh  juice.  It  is 
probable  that  the  activating  influence  of  bile  salts  is  due  to  some  physico- 
chemical  change  induced  in  the  digestion  mixture. 

One  may  ask  how  it  happens  that,  when  bile  and  pancreatic  juice  are 
both  absent  from  the  intestine,  the  fat  which  appears  in  the  feces  is  not 
neutral  fat  but  fatty  acid.  The  reason  is  that  the  neutral  fat  that  has 
escaped  digestion  in  the  small  intestine  becomes  acted  on  by  the  intestinal 
bacteria,  particularly  in  the  large  intestine.  Under  these  conditions, 
however,  the  fatty  acid  that  is  split  off  is  not  absorbed,  because  the 
epithelium  of  the  lower  parts  on  the  intestinal  tract  can  not  perform  this 
function. 

Besides  assisting  the  action  of  lipase,  bile  facilitates  fat  digestion  in 
other  ways.  Thus,  by  its  containing  alkali  and  mucin-like  substances 
it  assists  in  the  emulsification  of  fat.  Although  emulsification  is  no  es- 
sential part  of  fat  absorption,  yet  it  greatly  facilitates  the  process  by 
breaking  up  the  fat  into  small  globules  on  which  the  lipase  can  act 
much  more  efficiently.  The  alkali  also  combines  with  the  fatty  acids, 
as  they  are  liberated  by  the  digestive  process,  to  form  water-soluble 
soaps,  which  are  readily  absorbed  by  the  epithelial  cells.  The  bile  salts 
further  assist  in  the  solution  of  the  fatty  acids,  and  they  lower  the  sur- 
face tension  of  fluids  in  which  they  are  contained  and  so  bring  the  fat 
and  lipase  into  closer  contact. 

ABSORPTION  OF  FATS 

After  its  digestion  fat  lies  in  contact  with  the  intestinal  border  of  the 
epithelial  cells  as  fatty  acid  and  glycerine.  The  fatty  acid  is  combined 
either  with  alkali  to  form  a  water-soluble  soap,  or  with  bile  salts  to 
form  a  compound,  which  is  also  soluble.  The  glycerine  and  the  dissolved 
fatty  acids  are  separately  absorbed  into  the  epithelial  cells  of  the  in- 
testine, in  the  protoplasm  of  which — after  the  fatty  acid  has  been  set 
free  from  the  alkali  or  bile  salt — they  become  united  or  resynthesized 
to  form  neutral  fat,  which  gradually  finds  its  way  by  the  central  lac- 


692  METABOLISM 

teals  into  the  villi,  and  then  by  way  of  the  lymphatics  to  the  thoracic 
duct. 

The  chemical  explanation  of  the  absorption  of  fat  is  very  different  from 
that  formerly  held  by  histologists  who  maintained  that  the  fine  particles  of 
emulsified  fat  in  the  intestine  penetrate  by  a  mechanical  process  through 
the  striated  border  of  the  epithelial  cell  into  its  protoplasm.  The  histologic 
evidence  for  this  view  seemed  very  convincing,  for  fine  fat  globules  can 
readily  be  seen  in  the  epithelial  cells  of  the  intestine  after  fatty  food 
has  been  taken,  while  they  are  absent  during  starvation.  These  par- 
ticles seemed  to  have  passed  directly  from  the  intestinal  canal  into  the 
epithelial  cells  because,  when  the  fat  was  stained  with  characteristic  fat 
stains  before  feeding  it  to  the  animal,  the  globules  in  the  epithelial  cells 
were  found  to  be  similarly  stained.  The  supporters  of  this  mechanistic 
view  of  fat  absorption  maintained  that  the  appearance  of  the  stained  fat 
globules  in  the  epithelial  cells  could  not  be  explained  in  any  other  way 
than  by  supposing  that  the  fat  globules  had  wandered  unbroken  into 
the  epithelial  cells.  Such  a  conclusion  is,  however,  unwarranted,  for  the 
stains  that  are  soluble  in  fat  are  also  soluble  in  soap,  so  that  when  the 
fat  splits  up,  the  stain  will  remain  attached  to  the  soap  and  be  carried 
along  with  it  into  the  intestinal  epithelium. 

Absolute  proof  that  the  chemical  theory  is  the  correct  one  has  been 
supplied  by  a  large  number  of  experiments.  The  following  may  be 
cited:  (1)  When  the  lymph  flowing  from  the  thoracic  duct  is  examined 
after  feeding  with  fatty  acids  instead  of  neutral  fat,  it  is  found  to  contain 
only  neutral  fat,  indicating  that  a  synthesis  must  have  occurred  between 
glycerine  and  fatty  acid  during  the  absorption.  The  glycerine  for  this 
synthesis  is  furnished  from  sources  which  will  be  described  later.  (2) 
When  an  emulsion  made  partly  of  neutral  fats  and  partly  of  some  hy- 
drocarbon, such  as  albolene,  is  fed  and  the  feces  are  examined  for  these 
substances,  it  has  been  found  that  all  the  fat  but  none  of  the  hydrocar- 
bon is  absorbed ;  the  feces  contain  all  of  the  albolene  but  none  of  the  fat. 
This  experiment  supplies  very  strong  evidence  against  the  mechanistic 
theory,  for  microscopic  examination  of  the  above  described  emulsion 
shows  the  particles  of  neutral  fat  and  hydrocarbon  to  be  of  exactly  the 
same  size.  (3)  By  examining  the  properties  of  the  fatty  substances  in 
the  thoracic  lymph  collected  during  the  absorption  of  such  an  emulsion 
as  that  described  above,  nothing  but  neutral  fat  has  been  found  present. 
(4)  Similar  results  are  obtained  when  wool  fat,  which  is  an  ester  of 
cholesterol  and  fatty  acid,  is  fed. 

We  may  conclude  that  fatty  substances  which  are  insoluble  in  water  or 
can  not  be  changed  by  digestion  into  substances  (soap)  that  are  soluble 
in  water,  are  not  absorbed,  however  like  fat  they  may  be  in  other  particulars. 


FAT    METABOLISM  693 

The  chemical  theory  of  fat  absorption  further  explains  why  there  should 
be  such  large  quantities  of  soapy  substances  in  the  intestinal  contents, 

and  also  why  the  globules  of  fat  present  in  the  epithelial  cells  of  the 
intestine  are  so  very  much  smaller  than  those  which  lie  on  the  surface  of 
the  epithelium. 

It  might  be  objected  to  the  conclusions  just  stated  that,  although  unde- 
tectable, there  is  really  some  essential  physical  difference  between  emul- 
sified fat  and  emulsified  hydrocarbon.  In  order  entirely  to  prove  the  case 
for  the  chemical  theory,  it  is  necessary  to  feed  a  neutral  fat  possessing 
some  characteristic  that  depends  on  the  manner  of  union  existing  between 
fatty  acid  and  glycerine,  and  then  to  see  whether  it  appears  in  an  un- 
changed condition  in  the  thoracic  duct.  If  it  does  so,  the  fat  must  have 
been  absorbed  through  the  intestinal  epithelium  in  an  unbroken,  unsapon- 
ified  condition,  for  it  is  unlikely  that,  in  the  resynthesis  which  occurs  in 
the  intestinal  epithelium,  the  fatty-acid  molecules  would  recombine  with 
the  glycerine  molecules  in  exactly  the  same  manner  as  before. 

There  are,  however,  but  very  feAv  qualities  of  neutral  fats,  apart  from 
those  of  the  fatty  acids  which  compose  them,  by  which  they  can  be  char- 
acterized. The  most  likely  one  is  that  of  optical  activity.  None  of  the 
ordinary  fats  is  optically  active,  although  from  chemical  considerations 
it  is  quite  conceivable  that  some  should  be  so.  In  order  to  obtain  such  a 
fat  Bloor49  conducted  numerous  experiments  with  the  esters  of  stearic 
acid.*  In  a  series  of  experiments  Bloor  fed  isomannid-dilaurate,  a  syn- 
thetic fat  of  dextrorotatory  power  and  as  readily  absorbed  as  natural  fats, 
and  by  examination  of  the  neutral  fat  present  in  the  chyle  flowing  from 
the  thoracic  duct,  found  no  evidence  of  the  dextrorotatory  fat.  This  result 
confirms  previous  work  by  Frank,  who  found  that  the  ethyl  esters  of 
fatty  acids  are  not  absorbed  unchanged.  The  results  of  both  workers 
emphasize  the  probability  that  readily  saponifiable  fatty-acid  esters  do 
not  escape  saponification  under  the  favorable  conditions  of  the  normal 
intestine.  In  other  words,  had  the  fats  been  absorbed  unchanged,  as 
would  be  required  by  the  mechanistic  theory  of  fat  absorption,  they 
would  have  appeared  in  the  chyle  in  optically  active  conditions. 

These  most  important  conclusions  lead  us  to  inquire  as  to  the  reason 
for  the  change  in  fat  during  its  absorption.  It  can  not  be  for  the  purpose 
of  preventing  the  absorption  of  undesirable  fatty  substances,  such  as  the 
petroleum  hydrocarbons  or  the  wool  fats,  because  such  substances  are 
so  rarely  present  in  our  food.     It  is  most  probable  that  the  breakdown 


*Bloor  prepared  an  optically  active  mannitan  distearate,  hut  found  it  to  have  a  very  high  melt- 
ing point  and  to  be  only  half  as  digestible  as  the  ordinary  fats.  Its  absorption  was  too  slow  and 
unsatisfactory  to  make  it  suitable  for  the  above  purposes.  lie,  therefore,  proceeded  to  prepare  the 
di-ester  of  isomannitan  with  lauric  acid,  and  he  found  the  resulting  compounds  to  be  as  well-ab- 
sorbed as  ordinary  fat,  and  yet  to  possess  very  marked  dextrorotatory  power,  which,  of  course, 
they    lose    on   saponification.      This    fat   seemed    suitable,    therefore,    for    testing   the   above    question. 


694  METABOLISM 

and  resynthesis  of  neutral  fat  occurs  for  the  same  reason  that  similar 
processes  occur  during  the  absorption  and  assimilation  of  protein.  It 
will  be  remembered  that  protein  is  entirely  disintegrated  in  the  intestine 
into  its  so-called  building  stones.  These  are  absorbed  separately  into 
the  blood,  which  carries  them  to  the  tissues,  in  which  they  become  re- 
synthesized  to  form  the  body  protein.  And  so  it  appears  to  be  in  the 
case  of  fats.  The  process,  in  other  words,  permits  of  the  rearrangement 
of  fatty-acid  molecules,  as  a  result  of  which  the  newly  formed  fat  is  more 
adaptable  for  use  in  the  organism.  It  comes  to  be  more  like  the  char- 
acteristic fat  of  the  animal.  There  may  be  another  reason  for  the  proc- 
ess. It  will  be  remembered  that  lecithins,  which  constitute  the  most 
important  of  the  fatty  substances  of  the  cell  itself,  are  mixed  glycerides — 
that  is  to  say,  are  compounds  containing  a  variety  of  fatty  acids.  The 
rearrangement  of  the  molecules  of  neutral  fat  which  occurs  during  ab- 
sorption may  be  the  first  step  in  the  transformation  of  fat  into  lecithin. 

In  order  to  throw  further  light  on  the  question,  Bloor  has  performed 
a  number  of  interesting  experiments  in  which  the  chemical  properties 
of  fats  before  and  after  absorption  were  compared.  The  criteria  which 
he  took  were  melting  point,  iodine  value,  and  mean  molecular  weight; 
the  melting  point  representing  the  solidity  of  the  fat,  and  the  iodine 
value,  its  degree  of  unsaturation — that  is,  the  number  of  double  links  in 
the  fatty-acid  chain.  It  was  found  that  during  absorption  very  con- 
siderable changes  occur  in  these  two  characteristics ;  for  example,  when 
fat  with  high  melting  point  and  low  iodine  value  was  fed,  the  fat  in  the 
thoracic  lymph  was  of  distinctly  lower  melting  point  and  higher  iodine 
value.  When  fat  with  a  low  melting  point  and  a  high  iodine  value  was 
fed,  the  reverse  change  occurred,  for  the  melting  point  of  the  thoracic 
lymph  fat  was  higher  and  the  iodine  value  lower.  These  results  could 
be  explained  as  due  in  the  first  case  to  the  addition  of  oleic  acid  to  the 
fat  during  its  synthesis  in  the  intestinal  epithelium,  and  in  the  second 
case  to  the  addition  of  some  saturated  fatty  acid. 

When,  a  fat  consisting  mainly  of  glyceride  and  saturated  fatty  acid, 
but  with  a  low  melting  point,  was  fed,  the  addition  of  oleic  acid  was  still 
found  to  occur,  as  judged  from  the  iodine  value.  This  indicates  that  the 
change  is,  not  merely  in  order  that  the  melting  point  of  the  absorbed  fat 
may  be  lowered,  but  also  for  some  chemical  reason.  In  a  fourth  series 
of  experiments,  a  lowering  of  iodine  value  occurred  after  feeding  with 
cod-liver  oil,  which  contains  a  high  percentage  of  glycerides  of  highly 
unsaturated  fatty  acid. 

Evidently,  then,  the  intestine  possesses  the  power  of  modifying  the  com- 
position of  fat  during  its  absorption,  and  this  modification  is  apparently 
of  such  a  nature  that  it  causes  a  change  toward  the  production  of  a 


FAT    METABOLISM  695 

uniform  chyle  fat,  presumably  characteristic  of  the  animal  body.  The 
changes  arc  probably  greater  than  could  be  produced  by  admixture  of 
the  absorbed  fat  present  in  the  normal  fasting  chyle,  but  the  source  of 
the  oleic  acid  or  of  the  saturated  acid  required  for  this  synthesis  is  at 
present  unknown. 


CHAPTER  LXXVIII 
FAT  METABOLISM  (Cont'd) 

THE  FAT  OF  BLOOD 

Methods  of  Determination. — Normally  the  blood  contains  only  a  small 
percentage  of  fat,  but  after  a  fatty  meal  it  may  contain  so  large  an 
amount  that  the  fat  actually  rises  to  the  surface  of  the  blood  like  a  cream. 
By  means  of  the  ultramicroscope,  examination  of  the  blood  in  the  dark 
field  after  a  fat-rich  meal  reveals  the  presence  of  glancing  particles, 
the  so-called  "fat  dust."  These  particles  are  most  abundant  about  six 
hours  after  the  meal  has  been  taken,  and  they  gradually  disappear  by 
the  twelfth  hour.  They  do  not  appear  after  a  meal  when  the  thoracic 
duct  is  ligated.  They  disappear  Avhen  oxygen  is  bubbled  through  the 
blood. 

Fat  dust  has  also  been  found  abundantly  present  in  the  blood  of  em- 
bryo guinea  pigs  at  full  time,  but  not  in  the  mother's  blood.  This  -would 
indicate  that  the  placenta  must  have  the  power  of  taking  the  constitu- 
ents of  fat  from  the  mother's  blood  and  building  them  into  fat,  which 
then  passes  into  the  blood  of  the  fetus.  The  placenta  under  these  condi- 
tions acts  like  the  mammary  gland.  In  this  connection  it  is  of  interest 
that  there  is  also  much  fat  present  in  the  blood  of  pregnant  women.  The 
fat  content  of  the  placenta  is,  however,  greater  in  the  early  stages  of 
pregnancy  than  later. 

Although  these  facts  have  been  known  for  some  time,  it  has  been 
impossible,  either  on  account  of  the  large  quantities  of  blood  required 
for  a  chemical  examination  or  because  of  the  difficulty  in  estimating 
the  amount  of  fat  from  the  density  of  the  "fat  dust,"  to  follow  with  any 
great  degree  of  accuracy  the  exact  chemical  chanores  that  take  place  in 
the  fat  of  the  blood.  Recently,  however,  Bloor  has  succeeded  in  elab- 
orating methods  by  which  the  fat  content  of  the  blood  can  be  determined 
with  satisfactory  accuracy  in  small  quantities  of  blood,  so  that  a  con- 
tinuous series  of  observations  can  be  made  over  a  considerable  period. 

The  fat  is  extracted  from  the  blood  by  an  alcohol-ether  mixture  with  moderate  heat. 
An  aliquot  portion  of  the  filtrate  is  evaporated  in  the  presence  of  sodium  ethylate,  which 
saponifies  the  fat.  The  residue,  consisting  of  soap,  is  well  washed  and  then  treated 
with  hydrochloric  acid  so  as  to  precipitate  the  fatty  acid.     The  density  of  the  precipitate 

696 


PAT   METABOLISM  ■  G97 

tlms  produced  is  compared  in  an  optical  apparatus,  called  a  nephelometer,  with  a 
Btandard  solution  of  two  milligrams  of  oleic  acid  treated  in  the  same  way.  The  Patty 
acids  in  human  blood  are  mainly  oleic  and  palmitic. 

The  lecithin  and  cholesterol  may  also  be  estimated  in  the  same  blood  extract.  For 
lecithin  the  above  extract  of  blood,  after  the  removal  of  the  alcohol  and  ether,  is  digested 
by  heating  with  concentrated  H XO.,  and  ILSO,.  This  decomposes  the  lecithin,  liberating 
the  phosphorus,  a  solution  of  the  resulting  ash  being  rendered  faintly  alkaline  to  phenol- 
phthalein  and  then  slowly  added  to  a  silver  nitrate  solution.  The  density  of  the  pre- 
cipitate thus  produced  is  compared  in  the  nephelometer  with  that  of  a  precipitate  pro- 
duced in  the  same  amount  of  silver  nitrate  by  adding  to  it  a  standard  phosphoric  acid 
solution. 

For  cholesterol  an  aliquot  portion  of  the  above  extract  is  saponified  with  sodium 
ethylate  and  then  saturated  with  chloroform;  the  chloroform  extract  is  mixed  with  acetic 
anhydrid  and  II,KO,  (con.)  until  the  bluish  color  is  fully  developed  (Liebermann  reac- 
tion), the  intensity  of  which  is  then  compared  in  a  colorimeter  with  that  obtained  by 
similar  treatment  from  a  standard  cholesterol  solution. 

Variations  in  Blood  Fat. — In  the  dog  the  percentage  of  fat  in  the 
blood  is  remarkably  constant  under  normal  conditions.  After  a  fatty 
meal  the  increase  in  fat  begins  in  about  an  hour,  and  reaches  its  maxi- 
mum in  about  six.  The  increase  is  not  found  in  animals  in  which  the 
thoracic  duet  has  been  ligated.  Although  this  result  would  seem  to 
contradict  the  view  held  by  some  that  part  of  the  fat  which  can  not  be 
accounted  for  in  the  thoracic-duct  lymph  is  absorbed  by  way  of  the 
portal  vein,  it  does  not  by  itself  disprove  the  hypothesis,  for  it  has  been 
found  that  the  fat  content  of  the  portal  blood  is  always  higher  than  that 
of  the  jugular. 

Very  interesting  results  have  been  obtained  following  the  intravenous 
injection  of  emulsions  of  oil,  either  the  so-called  casein  emulsion  or  col- 
loidal suspensions.  Up  to  a  dose  of  0.4  gram  per  kilogram  of  body 
weight — which  by  calculation  would  suffice  to  raise  the  fat  content  of 
the  blood  by  100  per  cent — there  was  no  increase  in  fat  content.  In  or- 
der to  explain  this  disappearance  of  fat,  it  might  be  imagined  that  the 
injected  fat  particles  formed  emboli  in  the  smaller  capillaries.  Against 
such  a  view,  however,  is  the  fact  that  the  particles  of  fat  in  these  emul- 
sions are  one-half  to  one-seventh  the  size  of  a  red  corpuscle.  Although 
this  argument  is  no  doubt  of  some  weight,  it  should  be  remembered 
that  the  physical  condition  of  these  fine  fat  globules  is  not  the  same  as 
that  of  the  red  blood  corpuscle.  Their  surface  condition  may  be  such 
that  they  readily  agglutinate  so  as  to  form  small  masses,  which  may 
stick  at  the  branching  of  the  smaller  arterioles  and  capillaries.  Bloor 
himself  suggests  that  the  injected  fat  may  be  stored,  possibly  in  the  liver, 
since  the  fat  in  this  organ,  as  we  shall  see  later,  increases  under  similar 
conditions.    When  twice  the  above  quantity  was  fed  in  the  form  of  egg- 


698  METABOLISM 

yolk  fat,  some  of  it  persisted  in  the  blood  for  several  hours.  This  in- 
crease may  have  been  owing  to  the  flooding  of  the  temporary  storehouse 
with  fat,  or,  more  probably,  to  a  retarding  influence  that  lecithin  may 
have  on  fat  assimilation,  for  lecithin  itself  persists  in  the  blood  for  a 
long  time  after  intravenous  injection. 

During  fasting,  no  increase  in  blood  fat  was  found  unless  the  animal, 
by  special  feeding,  had  been  stuffed  with  excess  of  fat  prior  to  the  fast- 
ing period.  The  lipemia  in  this  case  indicates  that  fat  is  being  trans- 
ported from  one  place  to  another  to  serve  as  fuel  for  the  starving  tissues. 
Narcotics  were  found  to  produce  an  increase  in  blood  fat.  Ether  pro- 
duced this  increase  during  the  narcosis,  whereas  morphine  and  chloro- 
form did  not  do  so  until  after  recovery.  The  explanation  given  for  the 
ether  effect  is  that  a  mixture  of  blood  and  ether  has  higher  solvent  power 
for  fat  than  blood  alone.  The  explanation  for  the  chloroform  and  mor- 
phine effects  is  that  a  certain  amount  of  breakdown  of  the  tissue  cells, 
in  which  lipins  are  set  free,  supervenes  upon  the  action  of  these  narcotics. 

The  blood  fat  also  becomes  enormously  increased  in  about  forty  hours 
after  the  administration  of  phlorhizin,  and  on  the  second  or  third  day 
after  the  administration  of  phosphorus.  The  special  significance  of 
these  facts  we  shall  consider  later  in  connection  with  the  relationship  of 
the  liver  to  fat  metabolism. 

By  comparison  of  the  fatty  acid,  lecithin,  and  cholesterol  contents  of 
blood  during  fat  absorption,  it  has  been  found  that  there  is  a  steady  but 
very  variable  increase  in  fatty  acid,  accompanied  by  no  variation  in 
cholesterol,  but  with  an  increase  in  lecithin,  which  varies  from  10  to  35 
per  cent,  but  does  not  run  strictly  parallel  with  the  fatty-acid  increase. 
It  is  probable  that  this  increase  in  lecithin  represents  that  part  of  the 
absorbed  fat  which  is  intended  for  immediate  use  in  the  tissues  (page 
705).  The  more  or  less  independent  increase  in  lecithin  is  of  significance 
in  connection  with  the  fact  that  in  many  pathologic  conditions  of  so- 
called  lipemia  the  increase  does  not  affect  the  fats  of  the  blood  but  rather 
the  lipoids  (i.e.,  lecithin  and  cholesterol).  Separate  analyses  of  blood 
plasma  and  whole  blood  show  the  increase  of  lecithin  to  be  much  more 
marked  in  the  corpuscles  than  in  the  plasma,  whereas  the  fatty-acid 
increase  is  confined  to  the  plasma. 

To  illustrate  some  of  these  points  the  folloAving  table  will  be  of  value. 
In  it  is  shoAvn  the  average  distribution  of  fatty  acid,  lecithin  and  choles- 
terol in  normal  individuals  and  in  cases  of  diabetes,  in  which  disease, 
as  has  been  known  for  long,  there  is  marked  disturbance  of  fat  metab- 
olism. 


FAT   METABOLISM  699 

Blood  Lipoids  in  Normal  and  in  Diabetic  Persons 


NORMAL 
PER  CENT 

MILD 

MODERATE 

SEVERE 

DIABETES 

PER  CENT 

DIABETES 
PER  CENT 

DIABETES 
PER  CENT 

Fat  by  Blnor's         1 

Whole  Blood 

0.59 

0.83 

0.91 

1.41 

Method                 | 

Plasma 

0.62 

0.90 

1.06 

1.80 

r 

Whole  Blood 

0.37 

0.59 

0.65 

1.01 

Total   Fatty  Acids^ 

Plasma 

0.39 

0.64 

0.75 

1.28 

I 

Corpuscles 

0.34 

0.45 

0.48 

0.62 

r 

Whole  Blood 

0.30 

0.32 

0.33 

0.40 

Lecithin                    < 

Plasma 

0.21 

0.24 

0.28 

0.40 

I 

Corpuscles 

0.42 

0.42 

0.40 

0.40 

Cholesterol              J 

Whole  Blood 
Plasma 

0.22 
0.23 

0.24 
0.26 

0.26 

0.30 

0.41 
0.51 

1 

Corpuscles 

0.20 

0.21 

0.20 

0.24 

Glycerides                  1 

Plasma 
Corpuscles 

0.10 
0 

0.38 
0.18 

0.46 
0.23 

0.84 
0.38 

Total  Lipoids 

Plasma 

0.68 

0.98 

1.16 

1.98 

It  will  be  observed  that  there  is  about  0.7  per  cent  of  total  fatty  sub- 
stances in  normal  blood.  The  fatty  acids  (palmitic  and  oleic)  amount  to 
about  0.4  per  cent,  and  are  equally  distributed  between  plasma  and 
corpuscles;  the  lecithin,  about  0.3  per  cent,  being  twice  as  abundant  in 
corpuscles  as  in  plasma,  and  the  cholesterol,  0.2  per  cent,  about  equally 
distributed.  In  diabetes  all  of  these  substances  are  seen  to  be  increased 
in  proportion  to  the  severity  of  the  disease,  the  increase  being  mostly 
in  the  plasma.  The  increase  in  cholesterol  (confined  mainly  to  the 
plasma)  is  particularly  interesting,  since  the  substance  is  unaffected  in 
amount  by  excessive  feeding  with  fat. 

The  Destination  of  the  Fat  of  the  Blood. — In  general,  it  may  be  said 
that  the  blood  fat  is  transported  to  three  places :  (1)  the  depots  for  fat;  (2) 
the  liver;  and  (3)  the  tissues.  The  fat  present  in  each  of  these  places 
differs  from  that  in  the  others,  as  is  revealed  by  chemical  examination 
by  the  methods  described  on  page  687.  The  depot  fat  usually  yields'  about 
95  per  cent  of  its  total  weight  as  fatty  acid.  The  tissue  fat,  on  the  other 
hand,  yields  only  about  60  per  cent  of  its  total  weight  as  fatty  acid. 
This  difference  indicates  that  the  fatty  acid  must  be  combined  in  the 
tissues  with  a  much  larger  molecule  than  is  the  case  in  the  fat  of  the 
depots.  This  large  molecule  is  probably  that  of  lecithin  or  other  phos- 
pholipin,  and  the  smaller  molecule  in  the  depots,  that  of  neutral  fat. 
The  liver  fat  takes  an  intermediate  position  between  depot  fat  and  tissue 
fat  in  its  yield  of  fatty  acid.  "When  no  active  metabolism  of  .fat  is  go- 
ing on,  the  liver  fat  is  like  that  of  the  tissues ;  but  when  fat  metabolism 
is  active,  the  liver  fat  occupies  an  intermediate  position  between  liver 
fat  and  depot  fat. 


700  METABOLISM 

Another  difference  among  the  fats  in  these  three  places  is  with  regard 
to  the  degree  of  saturation  of  the  fatty-acid  radicles.  This,  it  will  be 
remembered,  is  indicated  by  the  iodine  value;  the  higher  the  iodine 
value,  the  greater  the  desaturation  of  fatty  acid.  In  depot  fat  this  value 
is  relatively  low — for  example,  about  30  in  the  goat  and  about  65  in  man ; 
depending  somewhat  on  the  fat  taken  in  the  food,  compared  with  which 
it  is  usually  a  little  higher.  The  fat  in  the  tissues,  on  the  other  hand, 
has  a  high  iodine  value,  possibly  110  to  130.  The  iodine  value  of  the 
fat  of  the  liver  is  remarkably  inconstant,  being  about  the  same  as  that 
of  the  tissues  when  fatty-acid  metabolism  is  not  particularly  active,  but 
approximating  that  of  the  depots  when  fat  mobilization  is  proceeding. 
The  significance  of  this  fact  we  shall  consider  later. 

The  Depot  Fat. — The  places  in  the  animal  body  where  depot  fat  is 
deposited  in  greatest  amount  are  the  subcutaneous  and  retroperitoneal 
tissues.  These  fat  depots  may  sometimes  become  of  enormous  size,  as 
in  the  case  of  the  famous  dog  of  Pfliiger,  of  whose  total  body  weight 
40  per  cent  was  due  to  fat.  Bloor  suggests  that  there  may  really  be  two 
different  types  of  fat  storage:  one  of  a  purely  temporary  character, 
Avhich  readily  takes  up  and  liberates  the  fat,  but  which  is  of  limited 
capacity  and  possibly  under  the  control  of  some  quickly  acting  regulat- 
ing mechanism,  like  that  of  the  glycogenic  function  of  the  liver;  and 
another  of  a  more  permanent  nature,  into  which  the  fat  is  slowly  taken 
up,  but  the  capacity  of  which  is  very  much  greater. 

Two.  questions  present  themselves  eoncerninsr  this  depot  fat:  (1)  where 
does  it  come  from,  and  (2)  what  becomes  of  it?  Regarding  the  source 
of  the  depot  fat,  there  is  no  doubt  that  it  comes  partly  from  the  fat  and 
partly  from  the  carbohydrate  of  the  food;  in  other  words,  it  is  either 
taken  ready-made  with  the  food  or  manufactured  in  the  organism.  That 
some  of  it  comes  from  the  fat  of  food  is  now  a  well-established  fact,  the 
evidence  for  which  need  not  detain  us  long.  The  best-known  experiment 
consists  in  first  of  all  starving  an  animal  .until  his  stores  of  fat  are 
nearly  exhausted  and  then  feeding  him  with  some  "ear-marked"  fat — 
that  is,  with  some  fat  having  a  characteristic  property  which  it  will 
not  lose  during  absorption.  It  will  be  found  that  the  depot  fat  thereby 
deposited  presents  many  of  the  qualities  of  the  fed  fat.  The  "ear- 
marking" of  the  fat  may  be  secured  by  using  fats  of  different  melting 
points,  such  as  mutton  fat,  which  has  a  high  M.P.,  or  olive  oil,  which  has 
a  low  M.P.  On  feeding  a  previously  starved  dog  with  mutton  fat,  the 
M.P.  of  the  depot  fat  approaches  that  of  mutton  fat — he  becomes  a 
dog  in  sheep's  clothing;  whereas  when  olive  oil  is  fed,  the  subcutaneous 
fat  becomes  oily.  Or  again  we  may  "ear-mark"  the  fat  by  combining  it 
with  bromine,  when  the  deposited  fat  will  likewise  be  brominized  fat. 


FAT    METABOLISM  701 

It  must  not  be  imagined,  however,  that  no  change  takes  place  in  the 
t'at  during  its  absorption  and  before  it  becomes  deposited  in  the  tissues. 

On  the  contrary,  the  stamp  of  individuality  is  put  upon  the  fat,  for,  as 
we  have  already  seen,  its  iodine  value  may  become  altered  and  its  melt- 
ing point  changed  during  the  process  of  absorption.  In  other  words, 
although  the  absorbed  fat  does  not  become  entirely  adapted  to  conform 
with  the  ordinary  qualities  of  the  depot  fat,  yet  it  tends  to  change  in 
this  direction. 

That  some  of  the  depot  fat  comes  from  carbohydrate  is  well  known  to 
stock  raisers.  When,  for  example,  an  animal  is  fed  on  large  quantities 
of  carbohydrate  and  kept  without  doing  muscular  exercise,  its  tissues 
become  loaded  with  fat.  If  we  desire  strict  scientific  proof  for  this,  we 
do  not  need  to  go  further  than  the  old  experiments  of  Lawes  and  Gil- 
bert, who,  it  will  be  remembered,  showed  that  the  fat  deposited  in  the 
tissues  of  a  growing  pig  is  greatly  in  excess  of  the  fat  that  could  have 
been  derived  from  the  fat  or  protein  which  was  meanwhile  metabolized. 
The  experiment  was  performed  on  tAvo  young  pigs  from  the  same  litter 
and  of  approximately  equal  weight ;  one  was  killed  and  the  exact  amounts 
of  fat  and  nitrogen  in  the  body  determined;  the  other  was  fed  for  several 
months  on  a  diet  the  fat  and  protein  contents  of  which  were  accurately 
ascertained.  When  after  four  months  this  pig  was  killed  and  the  fat 
determined,  it  was  found  that  much  more  had  become  deposited  than 
could  be  accounted  for  by  the  fat  and  protein  of  the  food,  even  suppos- 
ing that  all  the  available  carbon  of  the  protein  had  become  converted 
into  fat.  The  only  conclusion  is  that  the  carbohydrate  must  have  been 
an  important  source  of  the  extra  fat. 

The  Destination  of  the  Depot  Fat. — The  depot  fat  becomes  mobilized 
and  transported  by  the  blood  to  the  active  tissues  whenever  the  energy 
requirements  of  the  body  demand  it.  During  starvation,  as  we  have 
seen,  the  depot  fat  is  used  to  supply  90  per  cent  of  the  energy  on  which 
the  animal  maintains  its  existence.  Before  the  fat  is  transported,  it  is 
probably  broken  down  into  fatty  acid  and  glycerine,  as  which  it  passes 
through  the  cell  walls  to  be  again  reconstructed  into  neutral  fat  in  the 
blood.  What  agency  effects  this  constant  breakdown  and  resynthesis 
of  fat  it  is  difficult  to  say.  Two  ester-splitting  enzymes  are  present  in 
blood,  one  acting  mainly  on  simple  esters,  the  other  on  glycerides;  but 
it  has  been  impossible  to  demonstrate  any  evident  relationship  between 
either  of  them  and  the  extent  of  fat  mobilization. 

The  Fat  in  the  Liver. — The  physiology  of  the  liver  fat  has  been  very 
diligently  studied,  particularly  by  Leathes  and  his  pupils.50  The  out- 
come of  this  work  has  been  to  show  that  the  liver  occupies  an  extremely 
important  position  in  the  metabolism  of  fat,  being,  as  it  were,  the  half- 


702  METABOLISM 

way  house  in  the  preparation  of  the  fatty-acid  molecule  for  consumption 
in  the  -tissues.  Fat  is  a  material  containing  large  quantities  of  poten- 
tial energy.  While  in  the  depots  this  potential  energy  is  so  locked  away 
as  to  be  unavailable  for  tissue  use.  To  make  it  available  the  depot  fat 
is  carried  to  the  liver,  where  the  energy  becomes  unlocked  but  not  actu- 
ally liberated.  The  fat  is  then  transported  to  the  tissues,  and  the  libera- 
tion of  the  energy  occurs.  Neutral  fat  is  like  wet  gunpowder:  it  con- 
tains much  potential  energy,  but  not  in  a  suitable  condition  for  explo- 
sion. The  liver,  as  it  were,  dries  this  gunpowder,  Avhence  it  is  sent  to 
the  tissues  to  be  exploded. 

The  great  importance  of  the  liver  in  fat  metabolism  is  indicated  by 
comparison  of  the  percentages  of  fat — or  better  of  fatty  acid — contained 
in  it  under  different  conditions  of  nutrition.  In  the  ordinary  run  of 
slaughter-house  animals  the  liver  contains  from  2  to  4  per  cent  of  higher 
fatty  acid,  but  in  about  one  in  every  eight  animals  a  much  higher  per- 
centage will  be  found  to  occur.  The  same  is  true  in  laboratory  animals. 
In  the  case  of  the  human  liver  as  obtained  from  autopsies  in  certain 
classes  of  patients,  from  60  to  70  per  cent  of  the  dry  weight  of  the 
organ,  or  23  per  cent  of  the  moist  weight,  may  be  fatty  acid.  There  is 
no  other  organ  in  the  animal  body  that  is  ever  loaded  with  fat  to  this 
extent.  As  in  the  depots,  this  liver  fat  might  be  derived  either  from  fat 
carried  to  the  organ  from  elsewhere  in  the  body,  or  it  might  represent 
a  surplus  of  manufactured  fat. 

That  transportation  of  fat  to  the  livez  occurs  is  very  readily  demon-, 
strable  both  in  the  laboratory  and  in  the  clinic.  About  forty  hours 
after  giving  phlorhizin  to  a  dog,  it  has  been  found  that  enormous  quan- 
tities of  fat  appear  in  the  liver;  a  few  hours  later,  however,  this  excess 
of  fat  may  have  entirely  disappeared.  Fatty  infiltration  of  the  liver 
is  also  observed  in  phosphorus  poisoning,  although  in  this  case  the  fat 
usually  persists  till  the  death  of  the  animal.  In  man,  in  delayed  chlo- 
roform poisoning  and  in  cyclical  vomiting,  enormous  quantities  of  fat 
may  be  present  in  the  liver  within  a.  very  short  period  of  time  after  the 
onset  of  the  condition.  There  can  therefore  be  no  doubt  that  fat  is 
transported  to  the  liver  under  abnormal  conditions,  but  this  can  not 
be  taken  as  evidence  that  the  liver  has  anything  to  do  with  fat  metab- 
olism in  the  normal  animal.  Such  evidence  has  been  supplied  by  Coope 
and  Mottram,51  who  have  been  able  to  show  that,  at  least  in  rabbits,  a 
similar  invasion  of  the  liver  with  fat  occurs  in  late  pregnancy  and  early 
lactation.  They  also  found  that  the  fatty  acid  deposited  in  the  liver 
in  late  pregnancy  gives  an  iodine  value  which  lies  nearer  to  that  of  the 
mesenteric  fatty  acid  than  is  the  ease  in  normal  animals.  Mottram  con- 
cludes that  "wherever     .     .     .     there  is  abundant  fat  metabolism,  the 


FAT    METABOLISM 


703 


liver  is  found  to  be  infiltrated  with  fats,  presumably  to  be  handed  on 
elsewhere  when  worked  up."  It  is  interesting  that  the  Eetus  is  greedy 
of  unsaturated  fatty  acids. 

The  most  likely  source  of  the  fat  transported  to  the  liver  is  the  fat  pres- 
ent in  the  depots,  unless  when  digestion  is  in  progress,  when  it  may  be 
the  fat  from  the  intestine.  That  much  of  it  conies  from  the  depots  is 
easily  demonstrated.  Thus,  the  more  extensive  the  infiltration  of  the 
liver  with  fat,  the  more  closely  will  this  fat  be  found  to  agree  with  the 
depot  fat  in  its  chemical  characteristics.  This  has  been  very  clearly 
shown  by,  first  of  all,  starving  an  animal  so  as  to  clear  the  depots  of  fat 
as  much  as  possible;  then  feeding  it  on  some  "ear-marked"  fat  (unusual 
melting-point  or  a  brominized  fat)  ;  and  after  another  day  or  so  of 
starvation,  so  as  to  clear  the  liver  itself  of  fat,  poisoning  the  animal 
with  phosphorus  or  phlorhizin.  The  liver  will  be  found  shortly  after- 
wards to  be  invaded  with  fat  which  has  all  the  ear-marks  of  that  on 
which  the  animal  had  been  fed. 

Evidence  of  the  same  character  has  been  furnished  in  a  series  of  clin- 
ical cases  by  observations  on  the  amount  of  fat  and  the  iodine  value  of 
the  fatty  acid  of  the  liver.     This  is  shown  in  the  accompanying  table. 

Fatty  Acids  of  Liver 


CAUSE  OF  DEATH 


HIGHER  FATTY 
ACIDS  PER  CENT 
OF  DRY  WEIGHT 


IODINE  VALUE 
OF  FATTY  ACIDS 


1. 

Pernicious  anemia 

12.1 

116.8 

Normal 
figures 

9 

Lobar  pneumonia 

13.7 

116.8 

o 

Pernicious  anemia 

14.25 

116.0 

4. 

Diabetes 

14.4 

119.6 

5. 

Toxemic  jaundice 

15.6 

109.5 

Commencing 

6. 

Accident 

17.2 

103.5 

fatty 

7. 

Empyema 

21.5 

96.0 

change 

8. 

Phthisis 

25.4 

96.4 

'  9. 

Broncho-pneumonia 

38.4 

84.9 

10. 

Appendicitis 

44.0 

91.1 

Marked 

11. 

Carcinoma  of  bladder 

47.2 

77.8 

fatty 

12. 

Broncho-pneumonia 

54.6 

71.8 

change 

13. 

Ulcerative  colitis 

60.9 

80.3 

14. 

Accident 

66.3 

63.0 

15. 

Dysentery 

73.5 

69.1 

This  table  clearly  shows  that  the  more  fat  there  is  in  the  liver,  the 
nearer  this  fat  approaches  in  character  that  stored  in  the  depots. 

That  some  of  the  fat  in  the  liver  may  come  directly  from  the  fat  re- 
cently aosorhed  from  the  intestine  is  also  very  readily  demonstrable. 
Thus,  when  cocoanut  oil  was  placed  in  the  intestine  of  anesthetized  an- 
imals, along  with  bile  salts  and  glycerine,  it  was  found  by  Raper52  that 
30  per  cent  of  the  absorbed  oil  appeared  in  the  liver. 


704  METABOLISM 

The  characteristic  feature  of  cocoanut  oil  is  that  its  fatty  acids  are  volatile  in  steam 
and  are  saturated.  Some  of  the  fatty  acids  of  the  liver  are  volatile  in  steam,  but  they 
are  unsaturated.  By  distillation  in  steam  of  the  fatty  acids  obtained  by  saponification 
of  the  liver,  it  is  possible  to  determine  how  much  of  the  cocoanut  oil  has  passed  to  the 
liver. 

Similar  results  have  been  obtained  when  unsaturated  fatty  acids,  such 
as  those  contained  in  cod-liver  oil,  are  fed.  In  all  these  cases  the  rela- 
tionship of  the  liver  fat  to  that  of  the  food  is  even  more  evident  than 
that  between  food  fat  and  depot  fat,  because  in  the  liver  the  newly  absorbed 
fat  is  not  diluted  by  that  deposited  it  may  be  months  previously,  as  is 
the  case  in  the  connective  tissues. 

The  question  now  arises:  What  happens  to  the  fat  during  its  stay  in 
the  liver?  An  indication  of  the  nature  of  the  change  is  furnished  by 
observing  the  iodine  value  of  the  fat.  This,  it  will  be  remembered,  in- 
dicates the  degree  to  which  the  fatty  acid  is  unsaturated.  It  does  not 
necessarily  indicate  the  number  of  unsaturated  bonds  present  in  the  fatty- 
acid  molecule,  for  the  difference  in  iodine-absorbing  power  may  depend 
not  on  the  number  of  such  bonds  but  on  the  position  in  the  chain  at 
which  a  given  double  bond  is  inserted.  Even  Avith  this  reservation,  how- 
ever, it  is  evident  that  the  increase  observed  in  the  iodine  values  shows 
that  the  liver  has  the  power  of  desaturating  fat.  The  advantage  of 
this  change  depends  on  the  fact  that  the  desaturated  fatty  acid  will 
be  more  liable  to  break  up  than  the  saturated  fatty  acid.  In  other  words, 
the  double  linkage  will  weaken  the  chain  with  the  consequence  that  it  is 
liable  to  fall  apart  at  this  place;  such  at  least  is  the  natural  interpreta- 
tion which  the  chemist  would  put  on  the  result.  It  may  not,  however, 
be  the  correct  interpretation,  for  it  has  been  shown  that,  although  un- 
saturated fatty  acids  are  more  susceptible  to  chemical  change  in  the 
laboratory  than  saturated,  yet  when  fed  to  animals  they  appear  to  be 
more  stable  than  many  saturated  acids.  It  may  then  be  Avrong  to  con- 
clude that  the  introduction  of  a  double  linkage  in  fat  necessarily  means 
the  liability  of  the  fatty-acid  chain  to  break  at  that  point.  However 
.this  may  be,  it  seems  likely  that  one  function  of  the  liver  consists  in 
introducing  double  linkages  at  places  in  the  fatty-acid  chain,  as  a  result 
of  which  the  chain  breaks  at  these  places,  and  the  fragments  then  undergo 
further  oxidation. 

Double  linkages  may  be  introduced  not  only  in  one  place  in  a  fatty- 
acid  chain,  but  in  several.  For  example,  it  has  been  found  in  the  liver 
of  the  pig,  after  oxidizing  the  fatty  acids  with  permanganate,  that  oxida- 
tion products  are  obtained  indicating  the  existence  of  unsaturated  acid 
with  four  double  links.  Permanganate  (in  alkaline  solution)  is  used  for 
detecting  the  position  of  these  double  bonds,  because,  when  it  is  allowed 


PAT     METABOLISM  7<l.~> 

iii  act  on  unsaturated  fatty  acids  in  the  cold,  it  causes  hydroxy]  groups  to 

be  introduced   in  the  position   of  the  double  hoods.      When   the  oxidation   is 

performed  at  a  moderate  temperature,  (lie  fatty  acid  tails  aparl  at  the 
hydroxy]  groups.  A  fatty  acid  with  eighl  hydroxy]  groups  has  been 
obtained  in  tins  way  from  the  liver  of  the  pig.  The  presence  of  the  hy- 
droxy] groups  lias  been  confirmed  by  finding  thai  an  octobromide  is  ob- 
tained by  treatment  witli  bromine.  An  acid  of  the  same  formula  is  said  to 
bo  present  in  cod-liver  oil.  To  sum  up,  we  may  conclude  that  there  are 
certain  positions,  in  the  chains  of  carbon  atoms  which  const  it  ute  1  lie  fatty- 
acid  radicle,  where  the  liver  introduces  double  bonds,  and  that  the  weak- 
ened radicles  then  circulate  to  the  tissues,  -where  they  break  up  al  those 
positions. 

Rut  this  is  probably  not  the  only  way  in  which  the  liver  assists  in 
the  metabolism  of  fat.  It  may  also  lake  part  in  the  building  of  fatty- 
acid  radicles  into  the  complex  molecule  of  lecithin.  The  process  of  de- 
saturation  that  we  have  just  considered  is  probably  a  preliminary  step 
to  this  incorporation  of  the  fatty-acid  molecule  into  lecithin,  for  it  is 
well  known  that  lecithin  contains  highly  unsaturated  fatty-acid  radi- 
cles. In  support  of  such  a  view  it  is  interesting  to  note  that  in  alcohol- 
ether  extracts  from  normal  and  pathologic  livers,  the  lecithins,  which  are 
precipitated  by  acetone,  have  higher  iodine  values  (i.e.,  are  more  unsat- 
urated) than  the  neutral  fats  extracted  from  the  same  liver,  which  also 
have  higher  iodine  values  than  the  depot  fat  of  the  same  animal.  The 
desaturation  process  must,  therefore,  involve  the  fatty  acids  before  these 
beeome  built  into  the  lecithin  molecule. 

The  liver  is  probably  not  the  only  place  in  the  animal  body  where  the 
desaturation  of  fatty  acids  is  brought  about.  The  relative  activity  of 
the  different  tissues  in  this  regard  has  been  studied  by  feeding  cats 
with  fatty  fish  and  then  determining  the  iodine  value  of  fat  from  various 
plaees  in  the  body.  The  absorbed  fat  was  more  obvious  in  the  liver  than 
in  the  subcutaneous  tissues,  because  it  had  not  become  diluted  with  fat 
deposited  il  may  have  been  months  previously,  which  would  be  the 
ease  in  the  fat  of  the  fat  depots;  and  it  was  found  that,  although  the 
iodine  value  of  the  subcutaneous  fat  was  slightly  raised,  that  of  the 
liver  was  much  more  so,  indicating  that  the  desaturation  process  had 
been  more  active  in  this  organ,  but  had  also  occurred  to  a  certain  extenl 
in  the  depots. 

Before  leaving  this  subject  of  fat  in  the  liver,  it  is  important  to  re- 
call the  old  observation  of  Rosenthal,  that  a  more  or  less  reciprocal 
relationship  exists  betAveen  glycogen  and  fat  in  the  liver.  When  much 
glycogen  is  present  there  is  little  or  no  fat,  and  vice  versa.    It  is  impor 


700  METABOLISM 

tant  to  note  that  the  exact  locations  of  fat  and  carbohydrate  in  the  he- 
patic lobule  are  somewhat  different  in  the  two  cases. 

A  practical  clinical  application  of  the  above  work  is  found  in  the  fact 
that  fats  will  be  more  readily  utilized  by  the  body  when  they  contain  a 
high  percentage  of  unsaturated  fatty  acids.  It  is  probably  for  this 
reason  that  Norwegian  cod-liver  oil  is  of  such  undoubted  nutritive  value. 
It  is  much  more  so  than  Newfoundland  cod-liver  oil,  because  in  the  prep- 
aration of  this  variety  oxidation  occurs,  which  makes  it  no  longer  unsat- 
urated. Fish  oils  in  general  are  more  unsaturated  than  other  animal 
oils,  and  are  for  this  reason  more  nutritious. 

The  fat  in  the  tissues  differs  very  materially  from  that  of  the  liver  or 
the  depots.  Only  60  per  cent  of  this  fat  consists  of  fatty  acid,  which  is 
present  very  largely  as  part  of  the  lecithin  molecule,  thus  accounting  for 
the  high  iodine  value.  Some  is  probably  also  present  as  simple  glyceride. 
in  a  highly  unsaturated  and  therefore  very  fragile  condition. 


CHAPTER  LXXIX 
FAT  METABOLISM  (Cont'd) 

Two  very  important  questions  of  fatty-acid  metabolism  may  now  he 
considered:  namely,  (1)  how  is  fatty  acid  formed  from  carbohydrate? 
and  (2)  what  becomes  of  (lie  fragments  into  which  the  fatty-acid  molecule 
is  split  as  the  result  of  the  desaturation  process?  Although  these  prob- 
lems involve  chemical  details  of  a  somewhat  complex  nature,  we  must 
not  on  this  account  fail  to  consider  them;  for,  as  we  shall  see,  much  of 
Avhat  is  known  has  an  important  practical  application  depending  on  the 
fact  that  certain  of  the  intermediary  substances  may  accumulate  in  the 
organism  and  develop  a  toxic  action. 

The  Production  of  Fatty  Acid  out  of  Carbohydrate.— Tf  we  place  the 
formulas  for  glucose  and  palmitic  acid  side  by  side,  thus: 

CHX>PI-(CIIOH),-OHO  (glucose),  and 
CHS-  (CH.,)H-COOII  (palmitic  acid)  ; 

we  shall  see  that  this  transformation  must  involve:  (1)  a  considerable 
alteration  in  the  structure  of  the  molecule,  (2)  the  removal  of  oxygen, 
and  (3)  the  fusion  of  several  glucose  molecules  into  one  molecule  of  fatty 
acid. 

The  conversion  of  carbohydrate  to  fat  therefore  involves  a  process  of 
reduction,  and  the  resulting  molecule  must  be  capable  of  yielding  more 
energy  when  it  is  oxidized  than  the  original  one  of  carbohydrate,  for 
obviously  the  system  02  -  CII2  (which  corresponds  to  fat)  will  develop 
more  energy  than  that  of  0,  -  CHO  (which  corresponds  to  carbohydrate)  ; 
just  as  a  piece  of  wood  when  it  is  burned  will  develop  more  heat  than  a 
piece  of  charcoal.  This  explains  why  one  gram  of  fat  yields  9.3  calories 
of  heat,  and  one  gram  of  carbohydrate,  only  4.1  (page  535).  Fatty 
acid  therefore  contains  more  potential  energy  than  sugar,  and  in  explain- 
ing its  synthesis  from  sugar  in  the  animal  body  we  must  indicate  the 
source  of  the  extra  energy.  This  is  dependent  on  oxidation  of  some  sugar 
molecules — which  do  not  themselves  become  changed  to  fatty  acid — 
proceeding  side  by  side  with  the  reduction  which  affects  the  others  and 
represented  in  the  outcome  of  the  reaction  by  the  combustion  products 
C02  and  H20,  thus: 

6CfiH120G  +  13  02  =  20  C02  +  ClfiH3202  +  20  H20. 
(glucose)  (fatty  acid) 

707 


70S  METABOLISM 

What  evidence  have  wc  thai  such  a  process  actually  occurs  in  the  bodyt 
If  Ave  compare  the  intake  of  oxygen  with  the  output  of  carbon  dioxide 
in  the  respired  air,  we  shall  find  that  usually  there  is  less  of  the  latter; 

that  is  to  say,  the  respiratory  quotient,  as  this  ratio  is  called,  is  usually 
less  than  unity.  During  the  extensive  conversion  of  carbohydrate  into 
fat,  however,  which  occurs  during  the  fall  months  in  hibernating  animals, 
the  Jy.Q.  has  been  found  to  rise  as  high  as  1.4.  The  great  excess  of 
CO,  -  output  over  0,  -  intake  which  such  a  quotient  indicates  conforms 
with  the  above  equation. 

The  entire  dissimilarity  in  chemical  structure  between  the  molecules 
of  fat  and  carbohydrate  suggests  that  the  primary  step  in  the  conversion 
must  be  a  thorough  breakdown  of  the  carbohydrate  chain  into  compara- 
tively simple  molecules,  from  which  the  fat  molecules  are  then  recon- 
structed and  the  unnecessary  oxygen  set  free.  The  problem  is  to  ascer- 
tain the  chemical  structure  of  these  simpler  molecules  and  the  manner 
of  their  union  into  fatty  acid. 

Of  the  several  suggestions  which  have  boon  made,  that  of  Smodley""  seems  the  most 
likely.  As  will  be  seen  from  the  following  equations,  the  first  step  is  the  conversion  of 
glucose  to  pyruvic  acid  (page  600,  No.  1  in  equations).  By  enzymic  action  pyruvic 
acid  is  converted  into  acetaldehyde  (No.  2)  which  then  condenses  with  another  pyruvic- 
acid  molecule  to  form  a  higher  ketonic  acid  (No.  3),  from  which  by  the  loss  of  CO,., 
as  in  the  case  of  the  production  of  acetaldehyde  from  pyruvic  acid,  an  aldehyde  is  pro- 
duced (No.  4).  This  higher  aldehyde  behaves  like  acetaldehyde  in  again  combining  with 
pyruvic  acid,  forming  a  still  higher  ketonic  acid;  and  so  on  until  at  last  a  long  fatty- 
acid  chain  is  built  up,  thus: 

( 1 )  CaUrjOe  +  O,  =  2CHCOCOOH  I  2ir.o 
(glucose)  (pyruvic  acid) 

(2)  cn,cocooii  =  CILCHO  +  CO, 

(acetaldehyde) 

( 3 )  C  11,0110  1  CH.COCOOH  =  ('11  DC  1 1 : CHCOCOOH  +  H,0 

(unsaturated  ketonic  acid) 

(4)  CHX'H  :  CHCOCOOH  =  CH,CH:CHCHO  +  C02;  and  so  on. 

(higher  aldehyde) 
(5)  From  the  ketonic  aldehyde  formed  at  any  stage,  an  unsaturated  fatty  acid  (with 
one  less  C-atom)  is  readily  formed,  and  this  by  taking  up  II  may  become  saturated: 
CHjCH:CH  CO  C001I  +0  =  CIT3  CH:CH  COOH-f  C02. 

During  the  butyric-acid  fermentation  of  sugar  a  slightly  different  process  may  occur — 
namely,  the  lactic  acid,  which  we  know  is  readily  produced  from  glucose,  may  break  down 
into  acetaldehyde  (and  formic  acid),  and  two  such  molecules  condense  to  form  £-oxy- 
butyric  aldehyde;  and  this  again  condense  to  form  higher  fattj   acids,  thus: 

( 1 )  0,^,0,.  =  2CH,CHOHCOOH. 
(glucose)  (lactic  acid) 

(2)  2CILCHOHCOOH  =  2CH,CHO  +  II.COOII 

(acetaldehyde) 

(3)  2CHgCHO  =  CH3CHOHCH2CHO;  and  so  on. 

(/3-oxybutyric  aldehyde) 


PAT    METABOLISM  70!) 

That  higher  Patty  acids,  such  as  caproic  (CjH^O,)  and  caprylic  C,H„0  I,  have 
actually  been  isolated  Prom  the  products  of  this  Permentation  is  ;i  very  significant  Pact, 

and  ii  is  of  interesl  to  aote  that  Leathcs  1ms  somcti a  Pound  an  increase  in  higher  Patty 

acids  to  occur  during  the  aseptic  incubation  of  liver  pulp.  Unfortunately,  however,  the 
increase  of  Patty  acid  could  aot  1><1  shown  to  be  affected  by  adding  substances  to  the 
liver  which,  according  to  the  above  equations,  should  yield  Patty  acid. 

The  Method  by  Which  the  Fatty  Acid  is  Broken  Down.  In  the  chemi- 
cal laboratory,  ordinary  oxidizing  agents  attack  the  fatty-acid  chain  at  the 
C-atom  next  the  carboxy]  (COOH)  group  (the  alpha  C-atom).  1>ut 
this  can  not  occur  in  the  animal  body,  because  it  would  leave  behind  a 
smaller  chain  containing  an  uneven  number  of  ('-atoms,  and  such  chains 
are  never  found  present  in  the  animal  fats.  On  the  contrary,  the  com- 
moner fats  all  contain  an  even  number  of  ('-atoms  thus:  Butyric,  C4H802; 
palmitic,  C16H3202;  stearic,  C18H3602;  oleic.  C18H3402. 

The  intermediary  substances  which  are  produced  during  the  gradual 
breakdown  of  the  fatty-acid  molecule  in  the  normal  animal  are  of  a  very 
transitory  character  so  much  so  indeed  that  it  is  impossible  for  any  one 
of  them  to  accumulate  in  sufficient  amount  to  permit  of  isolation,  or  even 
detection,  by  chemical  means.  How  then  are  we  to  identify  the  inter- 
mediary products?  This  has  been  rendered  possible  by  the  discovery  thai. 
when  anything  occurs  to  disturb  the  normal  course  of  fat  metabolism.  ;is. 
for  example,  when  the  tissues  are  deprived  of  carbohydrates  (as  in  star- 
vation or  in  severe  diabetes),  the  oxidation  of  the  fatty-acid  chain  stnps 
short  when  a  chain  of  four  C-atoms  still  remains  unbroken.  These  hist 
four  C-atoms  seem  to  form  a  residue  that  is  more  resistant  to  oxidation 
than  the  remainder  of  the  fatty-acid  molecule.  It  is  a  residue,  therefore, 
which  is  quite  readily  further  oxidized  to  CO.  and  H20  under  normal  con- 
ditions, but  which,  although  incapable  of  becoming-  completely  oxidized 
when  the  metabolism  is  upset,  does  undergo  a  partial  oxidation,  result- 
ing in  the  production  of  various  intermediary  products.  These  accumu- 
late in  the  body  in  sufficient  amount  to  overflow  into  the  urine,  from 
which  they  can  be  isolated  and  identified. 

The  fatty  acid  with  4  C-atoms  is  butyric,  CH3CH2CH,COOH,  and  the 
first  oxidation  product  formed  from  it  in  the  body  seems  to  be  fi-oxybuty- 
ric  acid,  CH3CHOHCH2COOH.  This  then  becomes  oxidized  to  form  a 
body  having  the  formula  CH3COCH2COOH,  acetoacetic  acid,  which,  on 
further  oxidation,  readily  yields  CH3COCH3,  or  acetone.  These  sub- 
stances (/8-0xybutyric  acid,  acetoacetic  acid  and  acetone)  appear  in  the 
urine  during  carbohydrate  starvation,  as  in  diabetes. 

It  might  be  objected,  however,  that  a  chemical  process  occurring  under 
abnormal  conditions  need  not  also  occur  in  the  normal  animal.  That  i' 
probably  does,  however,  is  indicated  by  the  results  of  the  experiments 


710  METABOLISM 

of  Knoop  and  of  Embden  and  his  coworkers.  Knoop  conceived  the  idea 
of  introducing  into  the  fatty-acid  molecule  some  group  which  is  resistant 
to  oxidation  in  the  body.  The  phenyl  group  (CGH5)  was  found  to  have 
this  effect.  By  feeding  an  animal  with  the  phenyl  derivatives  of  acetic, 
propionic,  butyric,  and  valeric  acids,  it  was  found  that  the  urine  con- 
tained either  hippuric  (see  page  630)  or  phenaceturic  acid.  Both  of 
these  are  compounds  of  aromatic  acids  Avith  glycocoll  or  aminoacetic 
acid  (CH2NH;,COOH),  one  of  the  protein  building-stones  and  always 
available  in  the  organism  to  form  such  compounds,  thus: 

(1)  C„H5COOH  +  CHJNILCOOH  =  C6H6CONHCH2  COOH. 

(benzoic  (glycocoll)  (hippuric  acid) 

acid) 

(2)  CcH5CH2COOH  H-  CHJ^COOH  =  CcH5CH2CONHCH2COOH. 
(phenylacetic  (glycocoll)  (phenaceturic  acid) 

acid) 

When  either  benzoic  acid  (CfiH5COOH)  or  phenylacetic  acid  (C(!H5CH2- 
COOH)  is  formed  in  the  body  as  a  result  of  the  oxidation  of  phenyl 
derivatives  of  the  higher  fatty  acids,  the  acid  combines  with  glycocoll 
according  to  the  above  equations.  From  this  it  follows  that  if  oxidation 
occurs  so  that  two  C-atoms  are  thrown  off  at  a  time  (^-oxidation),  fatty 
acids  with  an  even  C-atom  chain  should  yield  hippuric  acid,  and  those 
with  an  uneven  chain,  phenaceturic.  This  was  found  to  be  the  case,  as 
the  accompanying  table  shows. 


oxidation" 

product 


EXCRETED  AS 


Benzoic  acid,  CcH5.COOH  Not  oxidized  Hippuric  acid 

Phenylacetic    acid,    C6IL .  CH2 .  COOH  Not  oxidized  Phenaceturic 

acid 
Phenylpropionic  acid,  C6H,.CH,.CH2.COOH  C6H5.COOH  Hippuric  acid 

Plienylbutyric  acid,  C,;H5 .  CH, .  CH2 .  CH2 .  COOH  C0H, .  CH, .  COOH  Phenaceturic 

acid 
Phenylvaleric  acid,  C0H5 . CH2 . CH2 . CH . CH2 . COOH       CcH\.COOH  Hippuric  acid 

(From  Dakin.)  . 

Embden 's  experiments  are  equally  convincing.  He  studied  the  forma- 
tion of  acetone  in  denbrinated  blood  perfused  through  the  freshly  excised 
liver.  Normally  only  a  trace  of  this  substance  is  formed,  but  when  fatty 
acids  with  an  even  number  of  carbon  atoms  were  added  to  the  blood, 
they  gave  rise  to  a  marked  increase  in  acetone,  whereas  those  with  an 
uneven  chain  failed  to  cause  any  change.  The  acetone  was  found  to  be 
derived  immediately  from  acetoacetic  acid.  The  following  table  shows 
the  results. 


FAT    MKTABOLISM  711 


FORMAL  PATTY   ACID  FORMATION  OB1 

AOETO  mi  in    ,\rn> 


A.cetic  acid  CH,.COOH 

Propionic  acid  CHj.CH^COOH 

I'.ut  vi  i<-  acid  CH3.CH2.CH2.COOH  + 

Valeric  add  CH„.(,n".Cir.,.CH.,.COOH 

Caproic  acid  CH3.CIi2.CH.*,.Cir..rir.,.COOH  + 

Eeptylic  acid  CH3.CH„.CH2.CH.".CH^CH.,.COOH 

Octoic  acid  CH,.<  M  I ...( 'II... <  'II ...<  Ml ...<  Ml"..<  H.COOIi  + 

Nonoic  acid  CH8.OH1.CHs.CH2.CH2.CHa.CH2.CH,.COOH 

Decoic  acid  CH, . CH, . CH, . CH„ . CH, . CH, .  CH2 . CH, . CH, .  CH, . COOH  + 

(From  Dakin.) 

For  a  long  time  it  was  difficult  for  chemists  to  understand  how  such 
a  process  of  oxidation  at  the  /?-C-atoni  could  occur,  since  they  were 
unable  to  bring  it  about  in  the  laboratory  by  the  use  of  the  ordinary 
oxidizing'  agents,  but  recently  Dakin  has  removed  the  difficulty  by  show- 
ing that  hydrogen  peroxide  (H202)  oxidizes  fatty  acids  just  exactly  in 
this  way. 

AVe  may  sum  up  the  results  of  these  experiments  and  observations  In- 
stating that  normal  saturated  fatty  acids  and  their  phenyl  derivatives  can 
undergo  oxidation,  not  only  in  the  animal  oody,  out  also  in  vitro,  in  such 
a  manner  that  the  two  (or  some  multiple  thereof)  termial  C -atoms  are 
removed  at  each   successive  step   in   their  decomposition. 

But  we  must  not  be  too  hasty  in  concluding  from  these  experiments  that 
the  steps  in  the  process  are  necessarily  in  the  order  of  first,  the  produc- 
tion of  a  ^-hydroxy  acid,  and  second,  the  oxidation  of  this  to  a  ketone 
group.  The  mere  presence,  side  by  side,  of  /3-hydroxybutyric  acid  and  of 
acetone  in  the  above  experiments  does  not  indicate  which  is  the  ante- 
cedent of  the  other,  and  indeed  there  are  several  experimental  facts  that 
seem  to  show  that  the  hydroxy  acid  may  be  derived  from  the  ketone. 
For  example,  when  acetoacetic  acid  is  added  to  minced  liver  and  the 
mixture  incubated,  /3-hydroxybutyric  acid  is  formed  (a  reduction  process), 
although  less  usually  the  reverse  action  (oxidation)  may  occur  when 
/^-hydroxy  acid  is  added.  A  reversible  reaction  must  therefore  be  capable 
of  occurring  between  these  two  substances,  thus: 

reduction 

CH3.CHOH.CH2.COOH  < CH3.CO.CH..COOH. 

oxidation 
(/3-oxybutyric  acid) *       (acetoacetic  acid) 

We  know  practically  nothing  as  to  the  conditions  determining  whether 
oxidation  or  reduction  shall  predominate,  but  there  are  two  significant 
facts  that  one  should  bear  in  mind:  (1)  that  a  plentiful  supply  of  oxy- 
gen is  necessary  for  the  oxidative  process,  and  (2)  that  the  presence  of 
readily  oxidizable  material  in  the  liver  (e.g.,  carbohydrates)  may  deter- 
mine the  direction  which  the  reaction  shall  take.  It  is  commonly  said 
that  fats  burn  in  the  fire  of  carbohydrates,  and  it  may  be  that  the  un- 


712  METABOLISM 

doubted  diminution  in  acidosis  which  occurs  in  diabetes  when  carbo- 
hydrate food  is  given  is  dependent  upon  the  directive  influence  which  its 
combustion  in  the  liver  has  on  the  above  processes.  But  we  must  be 
cautious  not  to  transfer  results  obtained  by  experiments  with  minced 
liver  in  judging  of  the  reactions  which  occur  during  life.  Provisionally, 
then,  we  must  assume  either  that  (8-hydroxybutyric  acid   is  a  necessary 

_••  in  the  oxidation  of  butyric  acid  or  that  it  is  formed  by  reduction 
of  acetoacetic  acid,  which  is  really  the  first  step  in  that  process. 

Of  course  there  is  no  evidence  in  the  above  experiments  that  the  higher 
fatty  acids  are  also  broken  down  by  the  removal  of  two  C-atoms  at  a 
time,  nor  has  it  been  possible  to  detect  any  ketonic  or  /3-hydroxy  deriv- 
atives of  them  in  the  animal  body.  We  can  only  reason  from  analogy 
that  a  similar  process  may  occur,  although  some  support  is  furnished 
for  such  a  view  by  the  fact  that  ketonic  fatty  acids  have  been  found  in 
vegetable   organisms. 

What,  then,  it  may  be  asked,  is  the  relation  of  the  desaturation  of  fatty 
acids  which  we  have  seen  occurs  in  the  liver  and  probably  elsewhere)  to 
the  /3  oxidation?  There  can  be  no  doubt  that  both  processes  can  occur 
in  the  animal  body,  indeed  in  the  same  organ,  e.g.,  the  liver:  and  it  is 
important  t<  sc  tain  their  relationship  to  each  other.  The  conclusion 
which  would  seem  to  conform  best  with  the  known  facts  is  that  the 
desaturation  process  occurs  (in  the  liver  so  as  to  break  up  the  lontr 
fatty-acid  chain  into  smaller  chains,  which  are  then  capable  of  ft  oxida- 
tion (in  the  tissues  ;  desaturation  may  be  the  process  by  which  the  mole- 
cule is  rough  hewn,  and  fl  oxidation  that  by  which  the  resulting  pieces 
arc  finally  split  to  their  smallest  pieces — that  is,  to  molecules  of  the  size 
of  acetic  acid,  which  an  finally  completely  burnt  to  carbonic  acid  and 
water. 

The  increase  of  iodine  value  ■     -  y  Loathes  and  his.  coworkers  need  not,  as  lias 

already  been  pointed  out,  necessarily  indicate  that  new  double  linkages  have  been  intro- 
duced in  the  fatty-acid  chain:  it  may  merely  indicate  that  structurally  isomeric  deriva- 
tives which  absorb  iodine  more  readily  have  been  formed.  Direct  evidence  of  desatura- 
tion has,  however,  been  offered  by  Hartley,  who  isolated  the  unsaturated  fatty  acids  (by 
•lissolving  the  lead  soaps  in  ether)  from  jug's  liver  and  then  proceeded  t>>  oxidize  them 
with  alkaline  permanganate.  "When  the  olein  of  the  depot  fat  is  thus  treated  at  a  low 
temperature,   two   hydroxy!   groups  become   attached   where   the   double   linkage   existed 

rming  dioxystearic  acid),  and  when  the  mixture  is  now  wanned,  the  molecule  splits 
into  two  at  this  place,  forming  two  lower  acids  (pelargonic  and  azelaic)  : 

I  i:         l  H.).CH:CH   CH,  :<'ooir: 
oleic  ;>■ 

on  on 

/  / 

2     <n   -(CHS)I-CH-  -CH HI    .moil: 

Tdioxystearic  acid  I 

(3)  fir      i  a    <<.<,!!    cooh-  (Ch.).cooh. 

hi  aic  acid) 


FAT    METABOLISM  713 

Wo  n i ; t \  conclude  from  this  that  the  double  Linkage  in  the  oleic  acid  of  the  depot  fat 
exists  between  the  ninth  and  tenth  C-atoms.  Bui  it  is  otherwise  in  the  case  of  i he  un- 
saturated acid  from  the  liver  (pig's),  for  under  the  above  process  of  oxidation  this 
yielded  caproic  acid,  which,  since  this  acid  has  six  C-atoms,  would  indicate  thai  the 
double  linkage  existed  between  the  sixth  and  seventh  C-atoms.  Another  interesting  fact 
broughl  in  light  by  the  experiments  was  thai  a  tetraoxystearic  acid  was  formed,  which 
fell  apart  in  surh  a  way  a<  to  indicate  that  the  hydroxy]  groups  occurred  between  flic  sixth 
ami  seventh  and  between  the  ninth  am!  tenth  C-atoms.  The  occurrence  of  this  substance 
would  In'  satisfactorily  explained  by  the  introduction  into  the  molecule  of  oleic  acid  of  a 
second  double  bond  -i.e..  between  the  sixth  and  seventh  C-atoms.  "The  acids  found  in 
the  pig's  liver  may  lie  accounted  for,  in  other  winds,  by  supposing  that  desaturation 
'd'  stearic  acid  ami  el'  the  ordinary  (depot)  oleic  acid  occurs  by  the  introduction  of  a 
double  link  between  the  sixth  ami  seventh  carbon  atoms  in  each  case" — (Leathes).  Still 
ether  double  links  may,  however,  In-  introduced  into  the  fatty-acid  chain,  for  acids  of  the 
linolic  acid  series  are  present  in  cod-liver  oil.  Finally,  it  is  of  interest  to  note  that  caproic 
acid  is  a  product  of  the  above  oxidation  process,  for  it  has  an  even  number  of  ('-atoms 
and  therefore  will   form  (8-Oxyblltyric  acid. 

To  go  into  these  chemical  problems  any  further  here  would  be  out  of 
place.  One  other  fact,  should,  however,  be  borne  in  mind — namely,  that 
the  unsaturated  acids  may  be  formed  from  saturated  acids  through  the 
intermediate  formation  of  /^-hydroxy  and  /?-ketonic  acids.  Their  mere 
presence,  in  other  words,  should  not  be  taken  as  evidence  that  the  oxida- 
tion of  fatty  acids  is  initiated  by  the  introduction  of  an  hydroxy]  group 
at  the  /?  position  in  the  chain. 


CHAPTER  LXXX 

CONTROL  OF  BODY  TEMPERATURE  AND  FEVER 

The  classification  of  animals  into  two  groups — warm-blooded  and  cold- 
blooded— according  to  their  ability  to  maintain  the  body  temperature  at 
a  constant  level,  is  more  or  less  arbitrary.  Between  the  two  groups  an- 
other exists,  represented  mainly  by  hibernating  animals,  in  which  at 
certain  times  of  the  year  the  animal  is  warm-blooded  and  at  other  times 
cold-blooded.  The  ability  of  the  higher  mammals  to  maintain  a  constant 
body  temperature  may  or  may  not  be  present  at  the  time  of  birth.  The 
heat-regulating  mechanism  of  the  human  infant  for  example  remains  ill 
developed  for  some  time,  so  that  exposure  to  cold  is  liable  to  lower  the 
body  temperature  to  a  dangerous  degree. 

VARIATIONS  IN  BODY  TEMPERATURE 

In  animals  in  which  the  heat-regulating  mechanism  is  fully  developed, 
there  is  not,  even  during  perfect  health,  entire  constancy  in  temperature 
in  the  different  parts  of  the  body  or  in  the  same  part  at  different  periods 
of  the  day.  The  average  rectal  temperature  of  man  is  usually  stated  as 
being  37°  C.  (98.6°  F.),  but  the  diurnal  variation  may  amount  to  1°  C, 
being  highest  in  the  late  afternoon  and  lowest  during  the  night.  There 
are  probably  several  causes  for  this  variation,  and  they  are  in  part  at 
least  dependent  upon  the  greater  metabolic  activities  of  the  waking 
hours  and  upon  the  taking  of  food.  Apart  from  these  influences,  how- 
ever, others  which  are  less  evident  appear  to  operate;  for  it  has  been 
found  that,  when  the  daily  program  is  reversed  by  night  work,  the  usual 
diurnal  variation,  although  much  less  pronounced,  still  remains  evident 
even  although  this  reversal  in  habit  may  have  been  kept  up  for  years. 
It  is  of  interest  to  note  in  this  connection  that  nocturnal  birds  have  their 
maximum  temperature  at  night  and  their  minimum  during  the  day. 

Regarding  the  temperature  in  different  parts  of  the  body,  that  of  the 
rectum  is  usually  about  1°  C.  higher  than  that  of  the  mouth,  and  this 
again  higher  than  that  of  the  axilla.  Of  these  three  the  mouth  tempera- 
ture is  the  most  variable,  for  many  conditions,  such  as  mouth  breathing, 
talking,  drinking  cool  liquids  and  even  exposure  to  cold  air,  are  sufficient 
to  lower  markedly  the  temperature  of  this  region.     AVhen  the  mouth 

714 


CONTROL   of    BODY   TEMPERATURE   AND   FEVER  715 

temperature  is  carefully  takes  by  leaving  the  bulb  of  the  thermometer 
under  the  tongue  for  a  minute  or  more,  it  is  practically  the  same  as  the 

temperature  of  the  arterial  bl 1  of  the  hand  when  tins  is  exposed  to  the 

ordinary  conditions  <>J'  outside  temperature.  Greater  differences  than 
1°  C.  in  the  temperature  of  differenl  regions  of  the  body  are  often  ob- 
served in  feeble  individuals  and  in  those  with  some  circulatory  disturb- 
ance. 

FACTORS  IN  MAINTAINING  THE  BODY  TEMPERATURE 

The  body  temperature  represents  the  balance  between  heat  production 
and  heat  loss.  The  production  is  effected  mainly  in  the  muscles  by  the 
oxidative  processes  which  are  constantly  ensuing  there.  When  the 
activity  of  the  muscles  is  abolished  by  paralyzing  the  terminations  of 
the  motor  nerves  with  curare,  the  temperature  of  warm-blooded  animals 
immediately  falls  or  rises  according  to  the  temperature  of  the  environ- 
ment. A  curarized  warm-blooded  animal  is  thus  made  to  behave  like  a 
cold-blooded  one.  Increased  muscular  activity,  on  the  other  hand, 
promptly  raises  the  body  temperature  by  1°  or  2°  C,  above  which,  how- 
ever, a  further  rise  does  not  occur,  provided  nothing  has  been  done  to 
interfere  with  the  mechanism  by  which  the  excess  of  heat  is  got  rid  of 
from  the  body.  The  temperature  in  such  cases  adjusts  itself  at  a  higher 
level,  at  which  it  remains  fairly  constant  however  strenuous  the  exer- 
cise. It  is  possible  that  a  certain  "amount  of  heat  may  also  be  generated 
by  the  chemical  processes  occurring  in  the  liver  and  other  viscera,  but 
when  compared  with  the  muscles  this  source  of  heat  is  undoubtedly  in- 
significant. Many  of  these  chemical  processes,  as  in  the  liver,  instead 
of  producing  actually  absorb  heat,  so  that  the  balance  between  heat- 
producing  and  heat-evolving  mechanisms  may  or  may  not  come  out  in 
favor  of  the  liberation  of  heat. 

The  production  of  heat  goes  on  all  the  time  in  muscles  on  account  of 
the  condition  of  tonic  contraction  in  which  they  are  held  (see  page  814), 
and  which  is  also  necessary  for  keeping  the  joints  in  the  proper  degree 
of  flexion  or  extension.  When  more  heat  is  required  by  the  animal  body, 
the  tone  of  the  muscles  increases  independently  of  the  function  which 
they  may  be  performing  in  controlling  the  position  of  the  joints.  This 
increased  tone  may  become  so  pronounced  that  it  causes  visible  contrac- 
tions, which  we  recognize  as  shivering.  Whenever  the  insensible  hyper- 
tonicity  and  the  shivering  arc  inadequate  to  produce  a  sufficient  amount 
of  heat,  the  animal  instinctively  moves  about  in  order  that  the  greater 
contractions  may  liberate  more  heat. 

The  heat  is  produced  in  the  muscles  by  oxidation  of  the  foodstuffs  that 
have  been  assimilated  from  the  blood.     Even  during  the  process  of  as- 


716  METABOLISM 

simulation  itself  a  certain  amount  of  heat  is  generated;  this  is  known 
as  the  specific  dynamic  action  of  the  foodstuff,  and  is  most  pronounced 
with  protein  and  least  so  with  carbohydrate  (page  538).  Advantage 
may  be  taken  of  this  heating  power  of  protein  to  produce  more  heat 
when  the  cooling  conditions  are  excessive;  in  winter,  for  example,  there 
is  an* inclination  to  take  more  protein  food  than  during  summer,  and  the 
per  capita  consumption  of  such  food  is  much  greater  in  peoples  living  in 
temperate  zones  than  in  those  living  in  the  tropics.  The  ultimate  amount 
of  heat  produced  by  oxidation  is  greatest  with  fat  and  least  with  carbo- 
hydrate. 

Heat  loss  in  man  is  effected  partly  through  the  lungs,  but  mainly 
through  the  skin.  Through  the  latter  pathway  heat  is  lost  by  the  physical 
processes  of  heat  conduction  and  radiation  and  by  the  evaporation  of  the 
sweat.  Through  the  lungs  it  is  lost  mainly  in  the  vaporization  of  the 
water  contained  in  the  expired  air  (latent  heat  of  vapor).  The  amount 
of  heat  lost  from  the  skin  by  conduction  and  radiation  depends  on  the 
temperature  of  the  skin,  which  again  depends  on  the  rate  at  which  the 
blood  is  circulating  through  the  cutaneous  vessels.  Under  ordinary  con- 
ditions of  external  temperature  two  or  three  times  as  much  heat  is  lost 
by  these  methods  as  by  evaporation.  The  losses  by  evaporation,  under 
conditions  of  rest  and  average  external  temperature,  are  about  equally 
divided  between  the  lungs  and  the  skin. 

From  all  these  facts,  it  is  evident  that  heat  loss  occurs  mainly  by  the 
skin  and  only  to  a  small  degree  by  the  lungs.  This  means  that  under 
average  conditions  in  man  the  main  regulation  of  heat  loss  is  effected  by 
variations  in  the  shin  temperature  brought  about  by  peripheral  vasocon- 
striction and  dilatation.  The  marked  sensitivity  of  the  cutaneous 
blood  supply  to  changes  in  the  temperature  of  the  environment  has  been 
very  clearly  shown  by  observations  made  with  the  hand  calorimeter  of 
Stewart  described  elsewhere  (page  281).  "When  the  bloodflow  througli 
the  hand  is  examined  in  a  person  who  has  been  exposed  to  the  outside 
air,  it  may  be  little  more  than  half  that  which  it  attains  after  he  has 
been  in  a  warm  room  for  some  time.  In  the  outside  air  the  vessels  con- 
strict to  prevent  heat  loss  by  conduction  and  radiation;  in  the  warm  room 
they  dilate  to  facilitate  this  loss.  The  afferent  impulses  which  reflexly 
control  the  change  in  the  cutaneous  blood  circulation  may  be  set  up  In- 
local  applications  of  heat  or  cold,  as  can  be  shown  in  the  hand-calorim- 
eter experiments  by  applying  a  cold  pad  to  the  skin  of  the  correspond- 
ing forearm,  when  an  immediate  curtailment  of  bloodflow  takes  place. 
Or  the  reflex  may  be  excited  from  distant  skin  areas,  as  illustrated  in 
the  curtailment  in  bloodflow  observed  when  the  opposite  hand  to  that 
on  which  the  observation  is  being  made  is  placed  in  cold  water.     The 


CONTROL    OF    BODY    TEMPERATURE     v\h    FEVER  717 

magnitude  of  the  change  in  cutaneous  circulation  is  nevertheless  depend 
cut  upon  the  extenl  of  the  area  of  the  body  thai  is  opposed  to  the  change 
in  temperature,  as  seen  in  the  dilatation  of  the  skin  vessels  prior  to  a 
rise  in  body  temperature  when  a   person  is  immersed  in  a  warm  bath. 

Although  afferent  impulses  Prom  the  skin  are  therefore  of  great  im- 
portance in  adjusting  the  cutaneous  blood  supply  according  to  the 
amount  of  surface  cooling  thai  has  to  occur,  a  further  effect  is  also  pro- 
duced on  tlioni  by  the  action  on  the  nerve  centers  of  temperature  dif- 
ferences in  the  blood  itself.  Thus,  when  the  temperature  of  blood  going 
to  the  brain  is  raised  by  placing  the  carol  id  arteries  on  some  heating  de- 
vice or  when  the  region  of  the  corpora  striata  is  directly  warmed,  the 
skin  vessels  become  dilated  as  if  the  animal  had  been  exposed  to  general 
warmth. 

When  the  loss  of  heat  by  radiation  and  conduction  is  no  longer  ade 
quate  to  prevent  a  rise  in  body  temperature,  or  when  the  processes  can 
not  operate  on  account  of  a  high  temperature  in  the  environment,  the 
loss  of  heat  from  the  skin  is  mainly  dependent  upon  the  evaporation  of 
sweat.  Under  ordinary  conditions  this  evaporation  takes  place  at  such 
a  rate  that  there  is  no  visible  perspiration  on  the  surface  of  the  body — 
the  so-called  insensible  perspiration.  When  the  heat  loss  by  this  channel 
must  become  greater,  the  perspiration  is  produced  in  larger  amount,  so 
that  it  collects  on  the  surface  of  the  body;  and,  provided  the  conditions  of 
the  environment  are  such  that  evaporation  can  readily  take  place  (low 
relative  humidity),  the  amount  of  cooling  of  the  body  that  can  be  effected 
becomes  very  great.  A  man  may  exist  without  any  marked  rise  in  body 
temperature  in  a  very  hot  environment  even  when  he  is  exposed  to  an  out- 
side temperature  that  is  the  same  as  that  of  his  body,  or  even  greater.  To 
encourage  evaporation,  however,  he  should  be  naked  or  very  lightly  clad, 
and  the  air  should  be  kept  in  constant  motion  so  that  the  layers  of  air 
next  to  the  skin,  which  ordinarily  very  quickly  become  saturated  with 
vapor,  are  transferred  and  replaced  by  dryer  air.  Movement  of  the  air 
also  increases  the  heat  loss  by  conduction,  provided  the  temperature  of 
the  air  is  not  too  near  that  of  the  body. 

The  importance  of  the  movement  of  air  in  the  regulation  of  heat  loss 
has  been  clearly  demonstrated  by  Leonard  Hill."4  F.  S.  Lee,  and  others,  who 
have  found  that  a  great  part  of  the  discomfort  experienced  by  living  in 
stagnant  air  can  be  obviated  by  putting  the  air  in  motion  by  electric  fans 
without  doing  anything  to  improve  its  chemical  purity.  In  one  famous 
experiment  a  number  of  young  men  were  placed  in  an  air-tight  cabinet 
at  the  ordinary  temperature  of  the  room.  After  a  time  they  began  to 
exhibit  the  symptoms  usually  attributed  to  polluted  air;  they  became 
drowsy  and  some  of  them  developed  headaches,  etc.     A  small  electric 


718  METABOLISM 

fan  was  then  started  so  as  to  set  the  air  in  motion.  Immediately  all  of 
the  men  recovered  and  remained  in  a  perfectly  comfortable  condition 
so  long  as  the  fan  was  kept  going.  The  practical  application  of  these 
facts  to  the  hygienic  control  of  the  working  conditions  in  mine  shafts, 
in  submarines,  in  workshops,  etc.,  will  be  self-evident. 

The  stimulus  to  increased  sweating  seems  to  be  dependent  mainly  on 
changes  in  the  temperature  of  the  blood ;  for  sweating  does  not  im- 
mediately set  in  when  the  body  is  subjected  to  heat,  as  by  a  warm  bath  or  a 
hot  pack.  It  usually  takes  from  ten  to  twenty  minutes  after  the  person 
has  been  placed  in  the  bath  or  surrounded  by  the  Avarm  blankets  of  the 
pack  before  sweating  becomes  pronounced.  It  can  usually  be  shown  that 
before  it  sets  in  the  body  temperature  has  been  raised  from  0.1  to  0.8 
degrees  C.  (0.2  to  1.4  degrees  F.).  In  this  regard,  therefore,  the  response 
of  the  sAveat  glands  docs  not  occur  so  promptly  as  does  the  dilatation  of 
the  cutaneous  vessels. 

Loss  of  heat  by  evaporation  of  sweat  occurs  only  in  certain  animals. 
It  is  practically  absent,  for  example,  in  the  dog.  The  degree  to  which 
it  may  occur  also  varies  in  different  individuals  of  the  same  species.  The 
power  of  withstanding  high  temperatures  is  proportional  in  man  to  the 
facility  with  which  he  perspires.  Where  sweating  is  interfered  with  by 
skin  diseases, — by  ichthyosis,  for  example, — exposure  to  heat  or  in- 
creased heat  production,  as  by  muscular  activity,  may  raise  the  body 
temperature  to  a  dangerous  degree. 

Another  factor  upon  which  the  efficiency  of  evaporation  of  sweat  in 
cooling  the  body  depends  is  the  relative  humidity  of  the  air.  "When  this 
is  high,  evaporation  of  water  into  it  can  not  occur,  and  it  is  on  this 
account  that  an  increase  in  body  temperature  is  much  more  likely  to 
occur  in  warm,  humid  atmospheres  than  in  those  that  are  dry.  At  the 
same  temperature  people  can  live  in  perfect  comfort  in  the  dry  air  of  the 
open  plains,  but  suffer  immediately  from  rise  of  temperature  when  they 
go  into  the  humid  air  of  the  river  valleys.  Similarly,  work  in  hot  fac- 
tories or  in  mines  is  quite  possible  at  very  high  temperatures  if  the  air 
is  kept  dry  and  in  motion,  but  becomes  impossible  when  the  air  is  moist. 
In  judging  of  the  adequacy  of  air  from  this  point  of  view,  it  is  there- 
fore important  to  take  not  the  ordinary  dry-bulb  thermometer  reading 
but  that  of  the  wet-bulb.* 

In  animals,  like  the  dog,  that  do  not  perspire  over  the  surface  of  the 
body,  vaporization  of  the  water  in  the  expired  air  is  the  most  important 
method  of  regulation  of  heat  loss.     When  such  an  animal  is  exposed  to 


*The  wet-bulb  thermometer  registers  a  temperature  that  is  lower  than  that  of  the  dry-bulb  in 
proportion  to  the  relative  humidity  of  the  air.  When  the  air  is  completely  saturated  with  moisture, 
the  temperature  recorded  by  the  two  instruments  will  be  the  same;  when  it  is  perfectly  dry,  the 
difference  will  be  maximal. 


CONTROL   OF    BOD?    TEMPERATURE    Wl>    FEVER  71!) 

warmth  or  when  the  region  of  the  corpora  striata  is  artificially  warmed, 
the  breathing  immediately  becomes  much  quicker  and  deeper,  so  thai 
pulmonic  ventilation  is  greatly  increased  and  much  more  water  is  carried 
out  as  vapor  with  the  expired  air.  To  vaporize  the  water  large  quanti- 
ties of  heat  are  required  (seen  in  the  latent  heat  of  steam).  Tn  man  this 
method  is.  ordinarily,  no1  of  great  importance,  but  it  may  become  so 
when  sweating  is  interfered  with,  as  in  ichthyosis.  The  more  rapid 
breathing  also  facilitates  cooling  by  increasing  the  conduction  of  heat 
from  the  mucous  membranes  of  the  tongue,  mouth,  throat,  etc.  The  im- 
portance of  this  method  of  cooling  has  been  shown  by  finding  that  after 
the  introduction  of  a  tracheal  cannula  a  dog  can  not  withstand  an  in- 
crease of  external  temperature  nearly  so  well  as  a  normal  animal. 

There  are  many  other  questions  concerning  the  control  of  heat  loss 
from  the  human  body  that  might  be  considered,  but  it  is  scarcely  nec- 
essary to  do  so  here.  It  should  be  added,  however,  that  the  relative 
humidity  of  the  air  in  the  control  of  heat  loss  has  a  different  significance 
when  the  temperature  is  high  from  that  when  it  is  low.  High  relative 
humidity  at  high  temperatures,  as  Ave  have  seen,  interferes  with  evapora- 
tion of  sweat,  whereas  high  relative  humidity  at  low  temperatures  in- 
creases the  heat-conducting  power  of  the  air  and  therefore  tends  to  cool 
off  the  surface  of  the  body  by  greater  conduction.  It  is  on  this  account 
that  it  is  much  more  comfortable  to  live  at  a  low  temperature  when  the 
air  is  dry  than  when  it  is  moist,  On  the  dry  plains  of  the  AVest  a  tem- 
perature of  many  degrees  below  zero  causes  less  sense  of  cold  to  be  ex- 
perienced than  in  the  moist  atmosphere  at  a  considerably  higher  tem- 
perature along  the  Great  Lakes  and  in  the  river  valleys. 

THE  CONTROL  OF  TEMPERATURE 

In  the  case  of  man  the  body  temperature  is  very  largely  under  volun- 
tary control,  as  by  the  choice  of  clothing  and  the  artificial  heating  of  the 
room.  Desirable  as  this  voluntary  control  of  heat  loss  may  be,  there  can 
be  little  doubt  that  it  is  often  managed  to  the  detriment  of  good  health. 
Living  in  overheated  rooms  during  the  cooler  months  of  the  year  so 
diminishes  the  loss  of  heat  from  the  body  that  the  tone  and  heat-produc- 
ing powers  of  the  muscular  system  are  lowered.  Not  only  does  this 
diminish  the  resistance  to  cold,  .but  it  causes  the  food  to  be  incompletely 
metabolized  so  that  it  is  stored  away  as  fat.  The  superficial  capillaries 
also  become  constricted  and  the  skin  bloodless  and  "pasty."  It  is  not 
looks  alone  that  suffer,  however,  but  health  as  well,  for  by  having  so 
little  to  do  the  heat-regulating  mechanism  gets,  as  it  were,  out  of  gear, 


720  MKTABOLTSM 

so  thai  when  it  is  required  to  act,  as  when  the  person  goes  outside  to 
the  cold  air,  it  may  not  do  so  as  promptly  as  it  should,  with  the  result 
that  the  body  temperature  falls  somewhal  and  catarrh,  etc.,  ate  the 
result.  There  can  be  little  doubt  that  much  of  the  benefit  of  open-air 
sleeping  is  owing  to  the  constant  stimulation  of  the  metabolic  processes 
which  it  causes. 

As  will  be  inferred  from  what  has  been  said  above,  the  control  between 
heat  production  and  heat  loss  is  effected  through  a  nerve  center  located 
in  or  near  the  corpora  striata.  In  most  animals,  when  the  spinal  cord 
is  cut  in  the  cervical  region,  the  body  temperature  quickly  falls  unless 
artifically  maintained.  In  the  case  of  man,  on  the  other  hand,  it  has 
usually  been  observed,  after  accidental  section  of  the  spinal  cord  in  the 
cervical  region,  that  a  rise  in  temperature  occurs.  In  twenty-four  un- 
complicated cases  of  spinal-cord  injury  in  man,  collected  from  the  rec- 
ords of  Guy's  Hospital  by  Gardiner  and  Pembrey,  it  was  found  that 
nineteen  showed  hyperthermia  (sometimes  amounting  to  43.9°  C.),  and 
only  five,  hypothermia  (sometimes  27.6"  C).  If  the  patient  lived,  the 
ultimate  effect  of  the  section,  as  in  the  lower  animals,  would  no  doubt 
be  the  loss  of  the  power  of  maintaining  a  constant  temperature. 

The  extent  to  which  the  animal  comes  to  behave  as  if  cold-blooded  after 
section  of  the  spinal  cord  varies  considerably  according  to  the  level  of 
the  lesion;  if  the  cord  is  cut  in  the  upper  thoracic  region,  for  example, 
the  regulation  against  cold,  although  distinctly  less  efficient  than  normal, 
is  far  better  than  when  the  section  is  made  through  the  cervical  cord. 
This  difference  is  dependent  on  the  fact  that  after  the  lower  lesion  much 
larger  muscular  groups  and  skin  areas  are  left  intact,  so  as  to  make 
regulation  possible.  Section  of  the  dorsal  cord  in  mice  has  been  found 
by  Pembrey  to  abolish  entirely  the  increased  metabolism  which  occurs 
in  normal  mice  when  they  are  exposed  to  cold. 

In  the  light  of  these  experiments  it  is  probable  that  the  difference  in 
the  effects  produced  on  body  temperature  by  section  of  the  cervical 
spinal  cord  in  man  and  the  lower  animals  depends  on  the  relative  im- 
portance of  the  heat-producing  and  heat-dissipating  mechanisms.  When 
the  control  of  heat  loss  is  paralyzed  in  the  smaller  animals,  the  cooling 
of  the  body  becomes  excessive  in  relation  to  the  amount  of  heat  produced 
in  the  paralyzed  muscles,  because  the  body  surface  is  extensive  in  com- 
parison with  the  body  weight  (see  page  55]  ).  In  the  Larger  animals  such 
as  man,  on  the  other  hand,  the  cooling  effect  is  much  less  marked,  espe- 
cially when,  as  is  common  after  such  an  accident,  the  patient  is  kept 
unusual lv  warm. 


CONTROL   OF    BOD'S    TEMPERATURE   AND    FEVER  721 

FEVER 

The  clinical  application  t>f  a  knowledge  of  the  mechanism  of  heat  regu- 
lation in  the  animal  body  concerns  the  causes  of  fever.  In  the  must 
familiar  form  fever  is  produced  by  in  feci  ions  processes,  but  it  may  also 
be  owing  to  various  other  causes,  among  which  may  be  mentioned  the 
parenteral  injection  of  foreign  protein,  excessive  destruction  of  protein 
substances  in  the  body  itself,  the  action  of  certain  drugs,  and  lastly, 
injury  to  the  base  of  the  brain  or  lesions  of  the  upper  levels  of  the  spinal 
cord.  Various  types  of  fever  are  recognized:  when  the  temperature  re- 
mains constantly  above  the  normal,  it  is  known  as  continuous  fever; 
when  oscillations  occur  but  the  temperature  never  falls  to  the  normal 
level,  it  is  known  as  remittent;  when  it  attains  the  normal  level  at  cer- 
tain periods  during  the  day,  it  is  known  as  intermittent. 

Causes  of  Fever 

During  a  sudden  rise  in  temperature  there  is,  on  the  one  hand,  in- 
creased heat  production  in  the  muscles,  and  on  the  other,  dimin- 
ished heat  loss  from  the  surface  of  the  body.  The  fever  is  therefore 
due  to  an  exaggeration  of  the  processes  ~by  which  the  body  normally  re- 
acts to  conditions  which  tend  to  lower  the  body  temperature.  The  increased 
muscular  activity  thus  induced  often  causes  visible  contractions,  familiar 
as  shivering;  and  the  constriction  of  the  cutaneous  blood  vessels  pro- 
duces the  subjective  sensation  of  chills,  and  causes  the  skin  to  become 
pale  and  cold  to  the  touch.  The  skin  muscles  also  contract,  producing 
"goose  skin."  During  this  stage,  objective  demonstration  of  the  cur- 
tailment of  the  skin  circulation  can  be  secured  by  observation  of  the 
bloodflow  through  the  hands  and  feet  (page  283).  When  the  temperature 
suddenly  falls  again,  the  crisis,  as  it  is  called,  muscles  become  flaccid 
and  produce  less  heat,  and  the  cutaneous  blood  vessels  dilate,  as  has 
been  shown  by  measurements  of  the  bloodflow  of  the  hands  and  feet. 
At  the  same  time  also,  the  sweat  glands  are  stimulated  and  marked  per- 
spiration occurs. 

Concerning  the  cause  of  continuous  fever,  it  must  be  assumed  that  the 
balance  between  heat  production  and  heat  loss  has  been  adjusted  at  a 
higher  plane  than  normal.  We  can  not  explain  the  fever  on  the  basis 
either  that  heat  production  is  permanently  increased  or  that  heat  loss 
is  permanently  diminished,  for  in  neither  of  these  cases  would  the  tem- 
perature stand  at  a  permanent  level  but  would  steadily  rise  or  fall,  ac- 
cording to  which  mechanism  was  disturbed.  While  set  at  this  higher 
plane  of  fever,  the  thermogenic  nerve  centers  are  still  capable  of  re- 
sponding in  the  usual  way  to  the  influences  which  cause  the  body  tern- 


722  METABOLISM 

perature  to  change  in  a  normal  person.  For  example,  when  a  fever  pa- 
tient is  subjected  to  a  hot  bath  so  that  his  body  temperature  rises  about 
0.2  to  0.5  degrees  C,  sweating  occurs  just  as  in  a  normal  individual;  or 
if  exercise  is  taken  the  increased  amount  of  heat  thereby  produced  in 
the  muscles  is  dissipated  in  the  usual  way.  When,  on  the  other  hand, 
the  patient  is  exposed  to  cold,  the  vessels  of  the  skin  contract  and  he 
shivers. 

Although  fever  is  not  caused  by  an  actual  disturbance  of  balance  be- 
tween heat  production  and  heat  loss,  neither  of  these  processes  is  pro- 
ceeding at  its  normal  level.  That  there  is  a  distinct  increase  in  the  total 
heat  production  of  the  body  in  acute  fevers  in  well-developed  persons 
has  been  shown  by  means  of  the  respiration  calorimeter.  This  increased 
heat  production  is  not  observed  in  patients  who  have  been  brought  into 
a  weakened  condition  and  in  whom  the  muscular  tissues  have  become 
atrophied  by  long-continued  fever.  The  increased  heat  production  in 
continuous  fever  is  mainly  dependent  upon  the  increase  in  body  tem- 
perature and  is  not  one  of  its  causes,  as  is  evident  from  the  fact  that  far 
larger  quantities  of  heat  are  frequently  produced  in  normal  individuals 
as  a  result  of  muscular  exercise  or  the  taking  of  large  quantities  of 
protein-rich  food.  The  heat  thus  produced  is,  hoAvever,  very  quickly 
dissipated,  so  that  only  a  temporary  rise  in  temperature  occurs,  (cf. 
Hewlett.57) 

Similarly,  it  can  be  shown  that  in  continuous  fever  there  is  a  relative 
inefficiency  in  the  mechanism  of  heat  dissipation.  "When  the  temperature, 
of  a  normal  person  is  artificially  raised  through  about  1°  C,  a  marked 
increase  in  cutaneous  bloodflow  and  profuse  perspiration  are  invariably 
noted.  In  a  patient  with  fever  of  the  same  degree,  on  the  other  hand, 
there  is  practically  no  change  in  the  skin  circulation;  indeed,  it  is  usually 
diminished,  and  there  is  no  unusual  perspiration.  The  heat-regulating 
mechanism  is  now  fixed  on  a  plane  that  is  higher  than  the  normal,  so 
that  although  further  increase  in  body  temperature,  as  we  have  seen, 
calls  forth  responses  like  those  in  a  normal  individual,  yet  at  the  fever 
temperature  itself  there  are  none  of  the  reactions  which  a  normal  individ- 
ual would  exhibit  if  his  temperature  were  artificially  raised  to  that  level.57 

The  adjustment  of  the  temperature  at  the  higher  level  is  by  no  means 
so  perfect  as  it  is  at  the  normal  level  of  health,  so  that  a  normal  subject 
is  more  resistant  to  the  effects  of  cold  than  is  a  patient  with  fever.  The 
degree  of  response  of  the  fever  patient,  however,  varies  considerably 
from  time  to  time ;  a  cold  bath  in  typhoid  fever,  for  example,  lowers  the 
body  temperature  much  less  effectively  at  an  early  stage  in  the  disease, 
when  the  fever  is  more  or  less  continuous,  than  later  when  it  is  becoming 
of  the  intermittent  type.    In  the  third  week  of  the  disease  the  cold  bath 


CONTROL   OF    BOD?    TEMPERAT1  RE     Wi»    FEVER  728 

more  readily  brings  down  the  temperature  and  keeps  ii  down  for  a  longer 
time  than  during  the  firsl  or  second  week.  The  mechanism  for  heat  loss 
is  also  deranged  in  fever,  which  explains  the  rise  in  temperature  that  is 
likely  to  follow  the  performance  of  even  moderate  muscular  exercise  or 
the  taking  of  too  hearty  a  meal  in  tuberculous  and  convalescent  typhoid 
patients. 

Changes  in  the  Body  During  Fever 

In  seeking  for  the  eause  of  fever  which  is  evidently  of  an  obscure 
nature,  it  is  necessary  to  collect  all  the  information  Ave  can  regarding 
the  metabolic  changes  that  are  then  occurring  in  llie  animal  body.  A 
few  of  the  most  significant  facts  that  have  so  far  been  collected  may 
be  mentioned  here.  Some  of  the  most  important  concern  the  dis- 
turbance in  nitrogenous  equilibrium  caused  by  the  considerable  loss  of 
nitrogen  which  takes  place  in  fever  patients  when  they  are  fed  on 
the  usual  hospital  diet  prescribed  for  such  cases.  This  loss  of  nitro- 
gen is  no  doubt  the  result  of  the  partial  starvation  in  which  the  pa- 
tient is  kept;  for  it  has  been  shown  by  Shaffer  and  Coleman""  that 
patients  with  typhoid  fever  may  be  maintained  in  nitrogenous  equi- 
librium by  feeding  them  with  relatively  large  amounts  of  carbohy- 
drate, which  acts  by  protecting  the  protein  of  the  body  from  disintegra- 
tion (see  page  571).  Even  with  a  diet  excessively  rich  in  carbohydrates 
that  no  more  than  covers  the  calorie  requirements  of  the  patient,  nitrog- 
enous equilibrium  has  also  been  attained.  The  protein  minimum  to 
which  fever  patients  can  be  reduced  is  nevertheless  considerably  higher 
than  the  minimum  in  normal  individuals. 

From  the  above  results  as  a  whole,  it  is  probably  safe  to  conclude  that 
there  is  a  specific  destruction  of  protein  going  on  in  the  body  during  fever. 
Further  evidence  of  such  a  destruction  is  furnished  by  the  presence  in 
the  urine  of  excessive  amounts  of  creatinin,  of  purine  bases,  and,  it  is 
said,  of  incompletely  hydrolyzed  proteins,  such  as  the  albumoses  (pro- 
teoses.) Moreover,  when  the  fever  suddenly  terminates  in  crisis,  there 
is  a  marked  increase  in  the  excretion  of  urea  (the  epicritical  urea  in- 
crease), which  indicates  that  an  extensive  deamination  of  protein  build- 
ing stones  (amino  acids)  is  occurring.  The  so-called  "diazo  reaction" 
obtained  in  the  urine  during  the  fever  is  also  believed  to  depend  on  the 
presence  of  abnormal  protein-disintegration  products. 

As  to  the  specific  cause  of  the  increased  protein  disintegration,  little 
is  known.  Several  factors  may  operate:  (1)  the  partial  starvation  of  the 
patient,  entailing  an  increased  breakdown  of  protein  to  meet  the  calorie 
requirements;  (2)  the  high  temperature,  which  in  itself  may  stimulate 
increased  protein  metabolism,  for  it  has  been  shoAvn  that,  when  normal 


724  METABOLISM 

animals  are  artificially  warmed,  protein  metabolism  becomes  increased; 
and  (3)  toxic  protein-decomposition  products  specifically  causing  an  ex- 
cessive breakdown  of  protein. 

Although  there  is  increased  protein  breakdown  during  fever,  it  must 
not  be  forgotten  that  only  about  20  per  cent  of  the  total  expenditure 
of  the  body  is  derived  from  this  foodstuff,  80  per  cent  coming  from  non- 
nitrogenous  material,  which  must  be  fat,  because  the  available  carbo- 
hydrates are  used  up  at  an  early  stage. 

Since  the  general  metabolism  is  increased,  the  excessive  breakdoAvn  of 
the  fatty  substances,  occurring  as  it  does  in  the  presence  of  a  diminished 
combustion  of  carbohydrates,  interferes  with  the  proper  oxidation  of  the 
fatty-acid  molecules  and  leads  to  the  appearance  of  so-called  acidosis 
products  in  the  urine,  and  consequently  to  a  relative  increase  in  the 
urinary  ammonia  (page  616).  A  tendency  to  acidosis  therefore  exists. 
The  acidosis  may  reach  a  considerable  degree  of  severity  and  cause  the 
tension  of  carbon  dioxide  in  the  alveolar  air  to  become  diminished.  Since 
a  similar  degree  of  acidosis  may  be  produced  in  partially  starved  ani- 
mals by  overheating  them  with  moist  air,  but  not  so  if  the  animals  are 
liberally  fed  with  carbohydrates,  it  is  probably  safe  to  conclude  that 
abundance  of  carbohydrate  is  advisable  in  the  food  that  is  furnished  to 
fever  patients. 

Another  interesting  metabolic  change  in  fever  concerns  the  salt  bal- 
ance. This  is  studied  by  observing  the  amount  of  sodium  chloride  excreted 
by  the  urine.  As  is  well  known,  this  becomes  markedly  diminished  until 
the  crisis  of  the  fever,  when  it  suddenly  increases.  Salt  retention  is  more 
marked  in  certain  types  of  fever  than  in  others,  and  it  is  essentially  dif- 
ferent in  nature  from  the  salt  retention  that  has  been  observed  to  occur 
in  nephritis.  This  difference  has  been  brought  to  light  by  examination 
of  the  chloride  content  of  the  blood.  In  nephritis,  the  concentration  of 
chlorides  in  the  blood  is  considerably  increased,  whereas  in  fever  it  is 
markedly  diminished.  The  deficiency  in  salt  elimination  can  not  be  at- 
tributed to  a  deficiency  of  salt  in  the  food,  for  it  sets  in  before  the  diet 
has  been  curtailed  and,  when  salt  is  given  to  a  febrile  patient,  it  is  re- 
tained in  the  body  to  a  greater  degree  than  is  the  case  in  the  normal 
individual.  For  some  reason  the  tissues  in  fever  have  acquired  the 
property  of  retaining  large  quantities  of  salt, 

Attempts  to  study  the  water  balance  during  fever  have  frequently  been 
made,  but  the  technical  difficulties  of  such  investigations  make  the  re- 
sults uncertain  and  of  little  value.  That  some  retention  of  water  occurs 
during  fever  is,  however,  evidenced  by  the  dilution  of  the  blood.  At  the 
crisis  this  hydremia  quickly  disappears  at  the  same  time  as  the  increased 


CONTROL   OF   BODY   TEMPERATURE    AND    FEVER  725 

elimination  of  chlorides  is  going  on.     Chlorides  and  water  -would  there- 
fore seem  to  behave  in  a  similar  fashion  during  fever. 

The  Heat-regulating  Center 

In  all  discussions  on  the  regulation  of  body  temperature  and  the 
causes  of  fever,  it  is  assumed  that  a  heat-regulating  or  thermogenic 
center  exists  somewhere  in  the  brain.  It  is  believed  to  be  located 
about  the  optic  thalami  or  corpora  striata,  for  it  has  been  found  in 
rabbits  that  destruction  of  the  brain  anterior  to  this  region  does  not 
cause  any  change  in  body  temperature,  -whereas  destruction  behind  it 
is  folio-wed  by  an  entire  upset  in  the  heat-regulating  mechanism.  Fur- 
thermore, artificial  puncture  of  this  part  of  the  brain  causes  marked 
elevation  in  body  temperature  in  rabbits  (heat  puncture).  Most  in- 
teresting experiments  have  been  recorded  by  Barbour."'6  who  succeeded 
in  applying  heat  or  cold  locally  in  the  region  of  the  centers.  By  the 
application  of  cold,  increased  muscular  metabolism,  on  the  one  hand, 
and  diminished  heat  loss,  on  the  other,  -were  excited;  and  conversely. 
when  warmth  was  applied,  an  increased  heat  loss  and  a  diminished  heat 
production  were  observed.  Irritation  of  this  region  of  the  brain  in  man. 
as  after  cerebral  hemorrhage,  is  also  accompanied  by  remarkable  dis- 
turbances in  heat  regulation.  It  is  believed  by  many  that  the  essential 
cause  of  infectious  fever  is  an  action  on  these  centers  by  toxic  substances 
which  develop  in  the  blood. 

The  centers  may  also  be  acted  on  by  various  drugs,  some  of  which 
excite  them  to  increase  the  body  temperature,  others,  to  lower  the  tem- 
perature when  this  has  already  been  elevated.  When  solutions  of  sodium 
chloride  are  injected  intravenously  or  subcutaneously  or  even  sometimes, 
particularly  in  children,  when  administered  by  mouth,  more  or  less  fever 
may  result.  This  must  be  a  specific  action  of  the  Na  ion,  for,  if  instead 
of  pure  solutions  of  NaCl.  solutions  containing  calcium  and  potassium 
salts  as  well  as  those  of  sodium  are  injected,  no  fever  is  induced.  This 
fact,  taken  along  with  the  close  similarity  between  puncture  diabetes 
and  heat  puncture,  lends  support  to  the  view  that  in  its  initial  stages 
experimental  fever  of  this  type  is  the  result  of  an  excessive  breakdown 
of  glycogen  in  the  liver.  It  must  not  be  imagined,  however,  that  persist- 
ent fever  can  be  attributed  to  such  a  cause,  since  the  fever  remains  after 
the  glycogen  has  all  been  removed.  Other  chemical  substances  produc- 
ing fever  are  caffeine,  certain  other  purines,  and  particularly  tetra-hydro- 
naphthylamin. 

Belonging  to  this  group  of  fevers  must  also  be  considered  the  im- 
portant ones  produced  by  the  intravenous  injection  of  certain  forms  of 
protein,  as  those  of  egg  white  or  those  derived  from  the  bodies  of  bac- 


726  METABOLISM 

tei-ia  or  from  the  laked  corpuscles  of  a  foreign  blood.  The  fever  in 
those  cases  is  no  doubt  caused  by  a  mechanism  closely  related  to  that 
responsible  for  anaphylaxis  (sec  page  89).  Such  injections  do  not  pro- 
duce fever  in  animals  after  division  of  the  cervical  spinal  cord  or  ex- 
cision of  the  midbrain.  It  is  believed  that  many  cases  of  so-called  asep- 
tic fever,  occurring  after  severe  contusions  or  other  wounds,  may  be 
the  result  of  destruction  of  proteins  within  the  body.  Similarly  the  rise 
in  temperature  during  infections  may  be  owing  to  the  breakdown  protein 
of  the  microorganism  in  the  cells. 

Significance  of  Fever  in  the  Organism 

It  is  impossible  at  present  to  state  definitely  whether  fever  is  a  re- 
action of  the  organism  against  some  infection  and  therefore  of  benefit 
in  assisting  the  organism  to  combat  it,  or  whether  it  is  in  itself  an  un- 
favorable condition.  The  question  can  certainly  not  be  answered  by 
observing  the  behavior  of  bacteria  growing  at  different  temperatures 
in  various  media  outside  the  body.  That  certain  bacteria  should  be 
found  not  to  thrive  at  incubator  temperatures  equal  to  those  found  in 
the  body  during  fever,  does  not  at  all  prove  that  this  fever  is  of  sig- 
nificance as  a  means  of  combating  the  growth  of  the  bacteria  in  the 
body.  It  is  undoubted  that,  where  the  body  temperature  becomes  ex- 
cessively high,  the  correct  treatment  is  to  keep  it  down  as  much  as 
possible.  On  the  other  hand,  the  reduced  mortality  that  has  followed 
the  introduction  of  the  cold-bath  treatment  in  typhoid  fever  may  not 
be  due  so  much  to  the  reduction  in  body  temperature  itself  as  to 
the  favorable  effect  produced  on  the  nervous  system  and  circulation. 
We  certainly  know  that  in  normal  animals  moderate  degrees  of  hyper- 
pyrexia produced  by  exposure  to  moist  heat  are  well  borne  for  consider- 
able periods  of  time,  thus  indicating  that  it  is  the  infection  and  not  the 
hyperthermia  that  causes  the  serious  damage  to  the  body  in  infectious 
fevers. 

METABOLISM  REFERENCES 

I  Monographs  and  Original  Papers) 

iLusk,  Graham:  The  Elements  of  the  Science. of  Nutrition,  W.  B.  Saunders  Co.,  ed. 
3,  1917. 

-f'atheart,  E.  P.:  The  Physiology  of  Protein  Metabolism,  Monographs  on  Bio- 
chemistry, Longmans,  Green  &  Co.,  1912. 

-Taylor,  A.  E.:     Digestion  and  Metabolism,  Lea  &  Febiger,  New  York,  11*11'. 

■^Underbill,  F.  P.:     The  Physiology  of  the  Amino  Acids,  Yale  Press,  New  Haven,  1915. 

"Macleod,  J.  J.  P.:     Diabetes,  Its  Pathological  Physiology,  E.  Arnold.  1913. 

saFurth,  von:  The  Problems  of  Physiological  and  Pathological  Chemistry,  etc.,  J.  B. 
Lippincott  Co.,  1916. 

"h.Jones,  W.:  Nucleic  Acids,  Monographs  in  Biochemistry.  Longmans,  Green  &  Co., 
1914. 

>  Mendel,  Lafayette  B. :     Ergebnisse  der  Physiologic,  1911. 


CONTROL  OP   BODY    TEMPEEATURE   AND   FEVER  727 

ALeathes,  J.  B.:     The   Fats,   M igrapha  in  Biochemistry,  Longmans,   Green  &  Co. 

Mathews,  A.  P.:    Physiological  Chemistry,  Wm.  Wood  &  Co.,  1917. 

Dakin,   H.   K.:      Oxidations  and  Reductions  in  the  Animal   Body,  Monographs  in  Bio- 

chemistry,  Longmans,  Green  &  Co.,  1912. 
BgLeathes,  J.  B.:     Problems  in  Animal  Metabolism,  1906. 
i;Du  Bois,  E.  P.,  and  collaborators:     Clinical  Chemistry,  Papers  1  to  25,  Arch.  Int.  fifed., 

L915-1  7.  xvi-xix. 
^Benedict,  F.  G.:     Am.  Jour.  Physiol.,  1916,  \li,  27.1  and  292. 
BMendel,  Lafayette  B.:     Harvey  Lecture,  J.  B.  Lippincotf  Co.,  1914-1915,  p.  101. 
•McCollum,  E.  V.,  and  collaborators:     Numerous  papers  in  Jour.  Biol.  Chem.,  be- 
ginning 1913. 
'"Hopkins,  F.  Gowland,  and  Willcock,  E.  G.:     Jour.  Physiol.,  1906,  xxxv,  88. 
"Bayliss,  W.  M.:     The  Physiology  of  Food  and  Economy  in  Diet,  Longmans,  Green 

&  Co.,  1917. 
•-McCollum,  E.  V.:     Harvey  Lecture,  Jour.  Am.  Med.  Assn.,  1917. 
isSweet,  J.  E.,  Carson-White,  E.  P.,  and  Saxon,  G.  J.:     Jour.  Biol.  Chem.,  1913,  xv, 

181;  ibid.,  1915,  xxi,  309. 
"Stepp,  W.:     Biochem.  Ztschr.,  1909,  xxii,  452. 
i^Funk,  Casimir:  m  Ergebnisse  der  Physiologie,  1915. 
isMcKillop,    M. :       Food    Values:      What    They    Are    and    How    to    Calculate    Them, 

Rutledge. 
I'iaMcCoy,  D.  Major:     The  Protein  Element  in  Nutrition,  E.  Arnold,  London,  1912. 
i^Pembrey,  M.  S.:     Chemistry  of  Respiration,  in  Schafer's  Text  Book  of  Physiology, 

1898,  i. 
isAllen,  F.  P.:     Glycosuria  and  Diabetes,  Boston,  1913. 
19Joslin:     Diabetes. 
-AVoodyatt,  R.  T.,  Sansum,  W.  D.,  and  Wilder,  R,  M.:     Jour.  Am.  Med.  Assn.,  1915, 

lxv,  2067.     Also  Taylor,  A.  E.,  and  Hulton,  F.:     Jour.  Biol.  Chem.,  1916,  xxv. 

173. 
-iMacleod,  J.  J.  R,,  and  Fulk,  M.  E.:     Am.  Jour.  Physiol.,  1917,  xlii,  193. 
—Hamman,  L.,  and  Hirschbaum:     Arch.  Int.  Med.,  1917,  xx,  761-788. 
23Cannon,  W.  B.:     Bodily  Changes  in  Pain,  Hunger,  Fear  and  Rage,  D.  Appleton  & 

Co.,  1915. 
24Knowlton,  F.  P.,  and  Starling,  E.  H.:     Jour.  Physiol.,  1912,  xlv,  146. 
25Patterson,  S.  W.,  and  Starling,  E.  H. :     Jour.  Physiol.,  1913,  xlvii,  135;  also  Cruick- 

shank  and  Patterson:     Ibid.,  p.  113. 
^Macleod,  J.  J.  R.:    Glycolysis,  Jour.  Biol.  Chem.,  1913,  xv,  497. 
27Murlin,  J.  R.:     Jour.  Biol.  Chem.,  1913,  xvi,  79. 
23Cruiekshank:     Jour.  Physiol.,  1913,  xlvii,  1. 

zsMacleod,  J.  J.  R.,  and  Pearce,  R.  G.:     Zentralbl.  f.  Physiol.,  1913,  xxvi,  1311. 
soWoodyatt,  R.  T.:     Jour.  Am.  Med.  Assn.,  1916,  lxvi,  1910. 
3i Van  Slyke,  D.  D.:     The  Present  Significance  of  the  Amino  Acids  in  Physiology  and 

Pathology,   Harvey   Lectures,  J.   B.   Lippincott  &   Co.,   1915-1916,   p.    146.     Also 

papers  in  Jour.  Biol.  Chem.,  1911,  ix,  185;  xii,  275;  ibid.,  1912,  xii,  301  and  399; 

ibid.,  1913,  xiii,  121,  125  and  187. 
32Folin,  O.,  and  Denis,  W. :     Jour.  Biol.  Chem.,  xi,  87  and  493;  ibid.,  1912,  xii,  14  and 

253. 
33 Abel,  J.  J.:     The  Mellon  Lecture,  Science,  1915,  xlii,  135. 

siHewlett,  A.  W.,  Gilbert,  L.  O.,  Wickett,  A.  D.:     Arch.  Int.  Med.,  1916,  xviii,  636. 
ssLosee,  J.  R.,  and  Van  Slyke,  D.  D.:     Jour.  Am.  Med.  Assn.,  1917,  cliii,  94. 
seShaffer,  P.  A.:     Am.  Jour.  Physiol.,  1908,  xxviii,  1. 
37Cathcart,  E.  P.:     Jour.  Physiol.,  1907,  xxxv,  500. 
ssMyers  and  Fine:     Jour.  Biol.  Chem.,  1913,  xiv,  9. 
39Levene,  P.  A.:     Cf.  W.  Jones.*o 
■toJones,  W.:     Nucleic  Acids,  Monographs  on  Biochemistry,  Longmans,  Green  &  Co., 

1914. 
"Benedict,  S.  R.:     Harvey  Lecture,  1915-16. 

*2Hunter,  A.,  and  Givens,  M.  H.:     Jour.  Biol.  Chem.,  1914,  xviii,  403. 
43Burian,  R-,  and  Schur,  H.:     Cf.  Macleod  in  Recent  Advances  in  Physiology  and  Bio- 
chemistry, ed.  by  Leonard  Hill,  E.  Arnold,  London,  1905. 
"Mendel,  Lafayette  B.,  and  Lyman,  J.  F.:     Jour.  Biol.  Chem.,  1910,  viii,  115. 
45Tavlor,  A.  E.,  and  Rose,  W\  C. :     Jour.  Biol.  Chem.,  1913,  xiv,  419. 
46Hopkins,  F.  G.,  and  Hope,  W.  B.:     Jour.  Physiol.,  1899,  xxiii,  277. 


728  METABOLISM 

i"Ascoli,  M.,  and  Izar,  G. :     Ztschr.  f.  Physiol.  Chem.,  1909,  lviii,  529;  ibid.,  1911,  lxiii, 

319. 
iSMcClure,  C.  W.,  Vincent,  B.,  and  Pratt,  J.  H.:     Am.  Jour.  Physiol.,  1916,  xlii,  596. 
*9Bloor,  W.  E.:     Jour.  Biol.  Chem.,  1912,  xi,  429;  ibid.,  1913,  xv,  105;  ibid.,  1914,  xvi, 

517;  ibid.,  1912,  xi,  141;  ibid.,  1915,  xxi,  421;   ibid.,  1914,  xix,  1;  ibid.,  1915, 

xxiii,  317;  ibid.,  1914,  xvii,  317;  ibid,  1915,  xxii,  133.    Also  Bloor  and  Knudson: 

Jour.  Biol.  Chem.,   1916,  xxvii,   107;   ibid.,   1916,  xxiv,  447;   Bloor,  Joslin  and 

Horner:       Ibid.,  1916,  xxvi,  417;  ibid.,  1916,  xxv,  577. 
soLeathes,  J.  B.:     The  Fat3,  Monographs  on  Biochemistry,  Longmans,  Green   &   Co. 
siCoope,  K.,  and  Mottram,  V.  H.:     Jour.  Physiol.,  1914,  xlix.  23;  ibid.,  1915,  xlix,  157. 
52Raper,  H.  S.:     Jour.  Biol.  Chem.,  1913,  xiv,  117. 
53Smedley,  I.  D.:     Proc.  Phys.  Soc,  Jour.  Physiol.,  1912,  xlv,  25. 
5*Hill,  Leonard:     Address  to  the  Phys.  Sec.  Brit.  Assn.  for  the  Adv.  of  Sci.,  Section, 

J,  1912. 
55Shaffer,  P.  A.,  and  Coleman,  W.:     Arch.  Int.  Med.,  1909,  iv,  538. 
seBarbour,  H.  G.:     Arch  f.  Exper.  Path.  u.  Pharmac,  1912,  lxx,  1.     Also  Barbour  and 

Wing,  S.  S. :     Jour.  Pharmac.  and  Exper.  Therap.,  1913,  v,  105. 
"Hewlett,  A.  W.:     Monographic  Medicine,  D.  Appleton  &  Co.,  1917,  i. 


PART  VIII 
THE  ENDOCRINE  ORGANS,  OR  DUCTLESS  GLANDS 


CHAPTER  LXXX1 
THE  ENDOCRINE  ORGANS,  OB  DUCTLESS  GLANDS 

In  order  that  the  various  activities  of  the  animal  organism  may  act 
efficiently  as  a  whole,  it  is  necessary  that  those  of  one  part  be  correlated 
•with  those  of  another.  This  correlation  of  function  is  mediated  either 
through  the  nervous  system  or  through  the  action  on  one  part  of  the 
body  of  substances  produced  in  another  part  and  carried  between  them  by 
the  blood.  Control  through  the  nervous  system  is  especially  developed  for 
those  functions  which  have  to  be  brought  promptly  into  play,  such  as 
muscular  movement  and  the  other  physiologic  processes  concerned  in  the 
adjustment  of  the  organism  to  quickly  changing  conditions  of  its  environ- 
ment. Control  through  the  blood  is  the  mechanism  by  which  the  metabolic 
activities  of  different  organs  are  mainly  correlated.  The  chemical  sub- 
stances involved  are  often  called  internal  secretions. 

Some  of  these  internal  secretions  are  merely  by-products  of  metabolism, 
and  are  only  incidentally  used  for  the  purpose  of  bringing  about  control 
between  different  parts  of  the  body.  To  this  group  belong  carbon  dioxide, 
which  may  act  on  the  respiratory  and  other  nerve  centers,  and  urea,  which 
may  stimulate  increased  activity  of  the  kidneys.  Indeed,  the  list  of  sub- 
stances included  under  such  a  definition  of  internal  secretions  is  almost 
illimitable,  and  to  designate  by  the  special  name  of  hormone  every  con- 
stituent that  can  affect  physiologic  functions,  as  some  have  done,  can  lead 
only  to  confusion.  The  internal  secretions  with  which  wre  are  more 
directly  concerned  are  those  that  are  specially  produced  for  the  purpose 
of  controlling  the  metabolic  functions.  They  are  given  the  general  name 
of  autacoids  (E.  A.  Schafer).60  Autacoids  may  be  either  the  sole  product 
of  some  special  gland  or  a  secondary  product  of  glands  which  have  other 
functions.  To  the  former  class  belong  the  autacoids  produced  by  the  para- 
thyroid, thyroid,  pituitary  and  adrenal  glands,  and  to  the  latter,  those 
produced  by  the  pancreas  and  generative  glands. 

Autacoids  have  further  been  subdivided  by  Schafer  into  tAvo  classes 

729 


730  THE   ENDOCRINE    ORGANS,    OK    DUCTLESS   GLANDS 

according  to  whether  they  excite  metabolic  processes  or  depress  them. 
Examples  of  excitatory  autacoids.  also  designated  as  hormones,  are  the 
epinephrine  produced  by  the  adrenal  glands,  which  excites  the  termina- 
tions of  the  sympathetic  nervous  system,  and  pituitrin  produced  by  the 
posterior  lobe  of  the  pituitary  gland,  which  excites  plain  muscular  fiber. 
Inhibiting  autacoids,  also  called  chalones,  are  not  so  commonly  known,  but 
are  illustrated  by  the  substance  contained  in  extract  of  the  placenta, 
which  tends  to  prevent  the  secretion  of  milk. 

Autacoids  may  have  either  an  immediate  or  a  delayed  action ;  the  effect 
which  they  produce  may  be  like  that  with  which  we  are  familiar  as  the 
result  of  stimulation  of  the  nerve  supply  of  a  gland,  being  illustrated 
again  by  the  effect  of  epinephrine,  or  they  may  act  so  slowly  that  it  is 
only  after  a  considerable  period  of  time  during  which  they  have  been 
in  the  organism  in  excess,  that  any  apparent  effect  is  produced.  The 
slowly  acting  autacoids  have  been  called  morphogenetic,  and  they  are 
well  illustrated  in  the  internal  secretions  of  the  anterior  lobe  of  the 
pituitary  and  of  the .  generative  glands — secretions  which  affect  growth. 

Regarding  the  chemical  nature  of  autacoids,  certain  facts  stand  out 
prominently.  Being  very  largely  the  products  of  "lands,  it  might  be 
imagined  that  they  would,  be  enzymic  in  nature,  for  enzymes  are  now 
known  to  be  the  most  important  active  agents  in  bioplasm  as  well  as  the 
active  agents  in  many  of  the  external  secretions,  like  those  of  the  sali- 
vary, gastric  and  intestinal  glands.  Autacoids,  however,  are  not  enzymes. 
They  are  far  simpler  in  chemical  structure,  and  are  not  destroyed  by 
heat  in  the  presence  of  water.  They  are  represented  by  a  comparatively 
small  molecule,  and  are  therefore  dialyzable.  This  latter  fact  justifies 
the  hope  that  it  may  be  possible  to  prepare  them  or  their  simpler  salts 
in  crystalline  form — a  hope  which  has  already  been  realized  in  the  case 
of  at  least  one  of  them — epinephrine.  Great  progress  has  likewise  been 
made  in  isolating  the  active  principles  of  the  thyroid  and  of,  the  anterior 
and  posterior  lobes  of  the  pituitary  glands.  To  sum  up,  then,  we  may 
say  that  an  autacoid  is  a  specific  organic  substance,  formed  by  the  cells 
of  one  organ  and  secreted  into  the  circulating  fluid,  which  carries  it  to 
other  organs,  upon  which  it  produces  effects  similar  to  those  drugs. 

Methods  of  Investigation 

To  investigate  the  function  of  an  autacoid,  careful  studies  are  made  of 
the  effects  produced  (1)  by  excision  of  the  gland  which  furnishes  the 
autacoid  and  (2)  by  administering  intravenously  or  subcutaneously  or 
orally  extracts  prepared  from  the  gland.  Frequently,  also  light  is  throAvn 
on  the  function  of  the  autacoid  by  observing  the  effect  which  fol- 
lows prolonged  feeding  with  the  endocrine  organ  that  manufactures  it 


Tin.    ENDOCRINE   ORGANS,    OB    Dl  CTLESS   GLANDS  731 

;iihl  by  observing  t lie  pathologic  changes  to  the  various  endocrine  organs 
in  diseased  conditions.  Embryologic  and  histologic  studies  are  also  of 
the  greatest  importance.  A  difficulty  in  investigating  the  function  of 
an  endocrine  organ  lies  in  the  fad  that  the  secretion  of  no  one  gland 
acts  independently  of  those  from  other  glands.  On  the  contrary,  there  is 
undoubtedly  a  close  association  of  function,  so  that  we  can  not  tell 
whether  a  change  of  fund  ion  observed  after  removal  of  some  gland  or 
administration  of  sonic  extract  is  a  direct  consequence  of  the  experi- 
mental procedure,  or  is  induced  by  some  secondary  effect  developed  on 
another  endocrine  organ.  It  will  no  doubt  take  many  years  before  suf- 
ficient data  have  been  collected  to  enable  us  definitely  to  state  what  the 
particular  function  of  each  endocrine  organ  may  be.  Since  most  progress 
has  been  made  in  connection  with  the  adrenal  gland,  it  will  be  advan- 
tageous to  consider  the  functions  of  this  gland  first. 

ADRENAL  GLAND 

In  mammals  the  adrenal  gland  is  composed  of  two  parts,  the  cortex  and 
•the  medulla.  In  other  groups  of  animals  however,  these  two  are  more  or 
less  separate,  being  completely  so  in  fishes.  This  not  infrequent  separa- 
tion of  cortex  and  medulla  suggests  a  different  function  for  the  two 
structures.     Experimental  investigation  supports  this  view. 

The  Cortex 

The  cortex  on  microscopic  examination  is  seen  to  be  composed  of  rows 
of  epithelial  cells  arranged  more  or  less  in  columns  except  at  the 
periphery,  where  they  form  glomerular  masses,  and  next  the  medulla, 
where  they  assume  a  reticular  formation.  The  cells  of  the  greater  part 
of  the  cortex,  unlike  those  of  the  medulla,  contain  no  granules  with 
special  staining  qualities,  but  they  do  contain  particles  which  are  be- 
lieved to  be  composed  of  cholesterol  esters  and  lecithin.  In  the  cells  of 
the  reticular  portion  of  the  cortex,  however,  pigment  particles  are  not 
infrequently  observed.  The  blood  supply  of  the  cortex  is  not  nearly  so 
rich  as  that  of  the  medulla,  being  represented  by  fine  arterioles  which 
i  un  inwards  from  the  capsule  towards  the  medulla  in  the  connective  tis- 
sue that  lies  between  the  columns  of  cortical  cells.  Nerves  similarly 
penetrate  into  the  cortex,  some  supplying  its  blood  vessels  and  cell 
columns,  but  most  of  them  proceeding  to  the  medulla.  They  are  derived 
from  a  network  of  nerve  fibers  in  the  capsule  of  the  organ,  and  the  nerve 
supply  of  this  network  conies  partly  from  the  suprarenal  plexus,  and 
partly  from  the  splanchnic  nerve.  Embryologically  the  cortex  is  de- 
veloped from  the  cells  of  the  irenital  ridge,  that  is,  from  mesoderms 
cells. 


732  THE   ENDOCRINE   ORGANS,    OR    DUCTLESS   GLANDS 

Very  little  is  known  concerning  the  function  of  the  adrenal  cortex, 
although  there  is  little  doubt  that  it  is  closely  related  with  the  develop- 
ment of  the  sexual  organs.  The  evidence  for  this  is  as  follows:  (1)  in 
cases  of  sexual  precocity  it  is  found  that  the  adrenal  cortex  is  much 
hypertrophied ;  (2)  it  becomes  hypertrophied  during  pregnancy;  (3)  it 
is  ill  developed  in  sexual  deficiency;  (4)  changes  occur  in  it  during  the 
estrual  cycle  in  many  animals;  (5)  after  castration  it  is  said  to  be  hyper- 
trophied; (6)  the  innermost  portion  of  the  cortex,  sometimes  called  the 
boundary  zone,  is  much  hypertrophied  in  the  human  fetus,  but  this  hyper- 
trophy entirely  disappears  after  the  first  year  of  extrauterine  life. 

Whether  the  cortex  possesses  other  functions  is  difficult  to  say.  Some 
facts  would  indicate  that  it  does.  For  example,  the  passage  of  blood 
through  the  cortex  before  reaching  the  medulla,  would  seem  to  indicate 
that  some  change  which  is  preparatory  to  the  main  change  occurring  in 
the  medulla  takes  place  in  the  blood  while  it  is  in  the  cortex.  This  view 
is  partly  substantiated  by  the  observation  that  when  an  excised  portion 
of  cortex  is  incubated  at  body  temperature,  a  substance  develops  in  it 
which  has  an  action  like  that  of  the  hormone  of  the  medulla — epi- 
nephrine. It  is  possible,  however,  that  this  action  is  due  to  the  fact  that  cer- 
tain of  the  decomposition  products  of  protein  develop  an  epinephrine- 
like  action  (see  page  502). 

The  Medulla 

Histologically  the  medulla  is  composed  of  masses  of  polygonal  cells 
with  blood  sinuses  between  them.  The  blood  supply  is  derived  from  ves- 
sels that  have  proceeded  to  the  medulla  through  the  capsule,  and  it  is 
extremely  rich,  being  indeed  the  richest  blood  supply  to  any  organ  in  the 
body,  greater  even  than  that  to  the  thyroid  gland.  The  nerves  form  a 
dense  plexus,  extending  into  and  between  the  secretory  cells.  The  most 
characteristic  feature  of  the  cells  composing  the  medulla  is  the  presence 
in  them  of  granules  which  stain  readily  with  chromic  acid,  and  are  hence 
often  called  chromaffin  cells.  There  are  also  some  cells  containing  coarser 
granules  that  are  soluble  in  water  and  do  not  stain  with  chrome  salts. 

Embryologically  the  medulla  is  developed  from  the  same  neuroblasts 
cells  that  give  rise  to  the  sympathetic  nervous  system.  This  evidence  of 
the  close  association  between  the  medulla  and  the  sympathetic  nervous 
system,  Ave  shall  see  to  be  substantiated  by  the  results  of  experimental 
investigation. 

On  account  of  the  anatomic  relationships,  it  is  impossible  to  study  the 
effect  of  excision  of  the  cortex  and  medulla  separately,  or,  indeed,  of  the 
action  of  pure  extracts  prepared  from  either  of  these  portions  of  the 


THE    ENDOCRINE   ORGANS,    OR    DUCTLESS   GLANDS  7:'..". 

gland.  Our  investigations  must  concern  the  effect  of  removal  of  the 
whole  gland  or  of  the  injection  of  extracts  of  i1  ;  but  as  we  proceed  to 
examine  the  data,  it  will  become  evident  that  most  of  ihe  effects  ob- 
served to  occur,  with  the  exception  of  those  already  mentioned  as 
definitely  associated  with  the  cortical  function,  can  be  attributed  to 
the  medulla. 

Adrenalectomy 

Excision  of  the  adrenal  gland  in  most  animals  is  very  quickly  fatal, 
the  only  well-known  exception  being  in  the  case  of  the  white  rat,  in  which 
excision  of  both  adrenals  may  not  be  incompatible  with  life.  For  some 
time  after  recovery  from  the  anesthetic  the  animal  upon  which  double 
adrenalectomy  has  been  performed  usually  behaves  in  a  perfectly  normal 
fashion,  although  it  may  be  less  lively  and  less  inclined  to  feed  than 
usual.  Very  soon,  however,  generally  within  twenty-four  or  forty- 
eight  hours,  definite  symptoms  of  muscular  weakness  are  apparent.  This 
weakness  soon  becomes  extreme,  and  is  accompanied  by  a  feeble  pulse, 
a  depression  of  body  temperature,  and,  later,  by  dyspnea.  After  an 
interval  which  is  never  longer  than  a  few  days,  death  supervenes,  being 
sometimes  preceded  by  convulsions. 

When  only  one  adrenal  is  removed,  very  few  animals  succumb ;  and 
if  some  time  is  allowed  to  elapse  so  that  the  immediate  shock  of  the 
operation  has  disappeared,  it  will  usually  be  found  that  removal  of  the 
remaining  adrenal,  although  ultimately  fatal,  is  not  so  quickly  so  as 
when  both  glands  are  removed  at  one  operation.  The  reason  for  this 
result  is  that  opportunity  is  given  for  a  compensatory  hypertrophy  of 
accessory  adrenal  bodies  to  occur.  Such  accessory  adrenal  bodies  may 
be  composed  of  cortical  or  medullary  tissue,  but  it  is  the:  latter  that  is  of 
importance  in  the  present  connection.  Chromaffin  tissue  is  found  in  most 
animals  along  the  front  of  the  aorta,  between  the  renal  arteries,  where  it 
can  usually  be  recognized  by  staining  the  tissue  with  chromic  acid. 
Sometimes  accessory  chromaffin  tissue  is  located  in  distant  parts. 
as  in  the  epididymis  of  the  rat,  for  example.  It  is  said  that  life  can 
be  maintained  if  one-eighth  of  the  total  amount  of  the  adrenal  substance 
be  present  in  the  body.  Attempts  to  prolong  life  after  adrenalectomy 
by  adrenal  transplantation  have  almost  invariably  met  with  negative 
results,  because  the  graft  undergoes  a  rapid  process  of  necrosis  and  dis- 
appears; although  it  is  said  that  transplantation  may  sometimes  be  suc- 
cessfully accomplished  if  the  grafting  is  done  into  the  kidney.  Adminis- 
tration of  suprarenal  extract  is  also  without  definite  benefit  after 
adrenalectomy. 


734  THE    ENDOCRINE   ORGANS,    OH    DUCTLESS   GLANDS 

Suprarenal  Extracts — Preparation 

Injection,  particularly  intravenous,  of  extract  of  the  adrenal  gland 
has  furnished  us  with  most  of  the  evidence  upon  which  our  knowledge 
regarding  the  function  of  this  organ  depends.  Such  an  extract  is  best 
made  by  grinding  the  entire  gland  with  fine  sand  in  a  mortar  and  then 
extracting  with  a  weak  (decinormal)  solution  of  hydrochloric  acid.  The 
extract  may  then  be  boiled,  filtered  through  muslin  and  nearly  neutral- 
ized, preferably  by  means  of  sodium  acetate.  If  kept  in  this  acid  reac- 
tion, the  active  principle  of  the  extract  does  not  materially  deteriorate 
with  time,  but  if  it  be  neutralized  or  considerably  diluted,  destruction 
due  to  oxidation  occurs,  as  evidenced  by  a  distinct  browning  of  the 
solution.  The  active  principle  of  such  extracts  has  been  isolated  in  a 
crystalline  form  (Takamine  and  Abel).  It  has  been  given  various  names 
(adrenalin,  suprarenin,  adrenin,  etc.),  but  the  tendency  is  definitelv 
towards  the  use  of  epinephrine.  Chemically,  epinephrine  has  been  found 
to  be  orthodioxyphenylethylolmethylamine. 

HO 


110  <^  ^>     *OTT(OII)  -  CH2NHCTI,. 

It  will  be  noted  that  it  is  closely  related  to  tyrosine  (see  page  604).  It 
is  also  closely  related  to  a  group  of  substances  (amines)  occurring  in 
putrid  meat  and  to  which  the  active  principles  of  ergot  belong.  It 
contains  an  asymmetric  carbon  atom  (asterisked  in  formula),  which 
indicates  that  there  must  be  three  varieties  of  epinephrine,  differing 
from  one  another  in  the  effect  which  they  produce  on  the  plane  of 
polarized  light  (i.e.,  a  dextro-  and  a  levo-rotatory  and  a  racemic  form). 

Epinephrine  can  be  prepared  by  synthetic  means,  the  first  product  of 
this  synthesis  being  the  racemic  salt,  which  can  then  be  split  by  appro- 
priate methods  into  dextro-  and  levo-  varieties.  The  levo-  variety  ap- 
pears to  be  identical  in  its  pharmacologic  action  with  the  natural  product. 
The  dextro-  variety  on  the  other  hand  has  only  poorly  developed  physio- 
logic activities  (about  seven  per  cent  that  of  the  levo-  variety),  while 
the  racemic  variety  comes  in  between  the  two  in  its  action.  A  valuable 
assay  of  the  amount  of  epinephrine  in  tissue  extracts  can  be  made  by 
the  method  of  Cannon,  Folin  and  Denis/'2  in  which  an  acid  extract  of 
the  gland  is  treated  with  phosphotungstic  acid,  and  the  blue  color  thereby 
developed  compared  colorimetrically  with  a  standard  blue. 

Physiologic  Action 

The  physiologic  effects  of  the  intravenous  injection  of  epinephrine  are 
markedly  excitatory  and  slightly  inhibitory  in  nature.     "We  will  consider 


Till      I  \ i;l.\i:    OHOANS,    OK    Dl  CTI.KSS    GLANDS  7:i") 

the  excitatory  action  first.    Immediately  after  the  intravenous  injection 

of  as  small  an  amount  as  000008  milligrams  per  kilogram  of  body  weight, 
a  distinct  pise  in  arterial  blood  pressure  may  be  observed.  It  is  quite  def- 
inite with  0 '00008  milligrams  per  kilogram,  and  is  accompanied  by  a 

slowing  of  the  pulse.  This  slowing  is  caused  by  stimulation  of  the  vagus 
center,  as  is  evidenced  by  the  fact  that  if  the  vagus  nerves  are  cut,  or 
sufficient  atropine  administered  to  paralyze  them,  the  same  dose  of 
epinephrine  produces  not  a  slowing  but  a  quickening  of  the  pulse,  and 
consequently  a  much  greater  rise  in  blood  pressure.  The  vagus  action 
is  developed  not  because  of  an  effect  of  epinephrine  on  the  vagus  center, 
but  secondarily  because  of  the  rise  in  blood  pressure. 

These  preliminary  experiments  indicate  that  the  locus  of  action  of 
epinephrine,  so  far  as  the  circulatory  system  is  concerned,  is  mainly  on 
the  small  blood  vessels,  constricting  them  and  thus  raising  the  peripheral 
resistance.  This  conclusion  can  readily  be  confirmed  by  applying  the 
epinephrine  directly  to  the  blood  vessels  of  the  exposed  mesentery,  or 
by  enclosing  a  vascular  organ  such  as  the  kidney  in  a  plethysmograph 
during  the  injection  of  epinephrine,  when  a  great  diminution  in  volume, 
accompanying  the  rise  of  arterial  blood  pressure,  will  be  observed.  The 
vasoconstricting  effect  of  epinephrine  does  not  become  developed  on  the 
large  blood  vessels  near  the  heart  on  account  of  the  deficiency  in  muscu- 
lar tissue  in  their  walls.  Indeed,  these  vessels  may  become  passively 
dilated  because  of  the  increased  blood  pressure.  The  arterioles  of  dif- 
ferent parts  of  the  circulation  are  not  equally  sensitive  to  epinephrine; 
those  of  the  splanchnic  area  are  most  sensitive,  whereas  those  of  the 
heart — the  coronary  vessels — do  not  respond  at  all  in  most  animals  (see 
page  257).  The  pulmonary  and  cerebral  vessels  have  a  variable  reactivity 
to  epinephrine. 

The  effect  on  the  vessels  persists  after  complete  destruction,  not  only 
of  the  central  nervous  system,  but  also  of  the  vasomotor  nerves;  epi- 
nephrine still  acts,  for  example,  on  vessels  the  nerve  fibers  of  which 
have  been  allowed  to  degenerate  by  cutting  them  several  days  before  the 
epinephrine  is  applied.  This  would  seem  to  indicate  that  the  epinephrine 
acts  directly  on  the  muscular  tissue  in  the  walls  of  the  blood  vessels, 
but  this  does  not  appear  to  be  the  case,  for  it  has  been  found  that  epi- 
nephrine is  incapable  of  acting  on  tissues  which  are  devoid  of  sympathetic 
nerve  fibers,  and  is  also  inactive  on  those  tissues  in  the  embryo  which  have 
not  yet  received  any  nerve  supply.  In  brief,  then,  although  epinephrine 
acts  only  on  blood  vessels  that  are  supplied  by  the  sympathetic  nervous 
system,  it  is  not  on  the  nerve  fibers  that  the  epinephrine  unfolds  its 
action.     We  shall  see  immediatelv  that  this  conclusion  is  in  conformitv 


73C>  THE   ENDOCRINE   ORGANS,    OK    DUCTLESS   GLANDS 

with  the  results  of  observations  made  on  structures  other  than  the  blood 
vessels. 

Other  muscular  structures  excited  by  epinephrine  are  as  follows: 
(1)  the  dilator  muscle  of  the  pupils,  especially  after  the  nerve  supply  has 
been  destroyed  by  extirpation  of  the  superior  cervical  ganglion;  (2)  the 
sphincters  of  the  pylorus  and  of  the  ileocecal  valve;  (3)  the  muscle  fibers 
of  the  spleen,  the  vagina,  the  uterus,  the  vas  deferens,  and  the  retractor 
penis.  Regarding  the  action  on  the  uterus,  however,  it  should  be  noted 
that  a  different  response  may  be  obtained  according  to  whether  the 
uterus  is  pregnant  or  not.  The  plain  muscles  of  the  orbit  and  globe  of 
the  eye  are  sometimes  excited  by  suprarenal  extract,  causing  the  eyes  to 
protrude,  the  palpebral  fissure  to  become  large  and  the  third  eyelid  to 
be  retracted,  changes  which  are  very  like  those  which  develop  as  a 
result  of  fright. 

Inhibitory  effects  of  epinephrine  on  muscle  are  exhibited  by  the  follow- 
ing: (1)  the  muscle  of  the  intestine;  (2)  the  stomach;  (3)  the  esophagus; 
(4)  the  gall  and  urinary  bladders. 

The  effect  of  epinephrine  in  inhibiting  the  rhythmic  contractions  of 
an  isolated  portion  of  the  intestine  in  oxygenated  Ringer's  solution  is  a 
very  striking  phenomenon,  and  one  which,  as  we  shall  see,  may  be  very 
successfully  employed  for  detecting  small  quantities  of  epinephrine. 
Extremely  dilute  solutions  of  epinephrine  increase  the  contractions. 

The  effects  of  epinephrine  on  glandular  structures  are  the  same  as  those 
which  would  be  produced  by  stimulation  of  the  sympathetic  nerve  supply 
of  the  gland.  Thus,  the  secretions  of  the  lachrymal  gland,  the  salivary 
gland  (in  the  cat),  the  mucous  glands  of  the  mouth  and  pharynx,  the 
gastric  but  not  the  pancreatic  glands,  can  readily  be  shown  to  be 
excited. 

From  these  results  as  a  whole,  it  is  evident  that  the  effect  of  epineph- 
rine on  muscles  and  glands  is  exactly  the  same  as  that  which  would  be 
produced  by  stimulation  of  their  sympathetic  nerve  supply.  This  paral- 
lelism of  action  between  epinephrine  and  the  sympathetic  nervous  sys- 
tem becomes  still  more  evident  when  we  consider  certain  of  the  changes 
in  metabolism  that  follow  administration  of  epinephrine.  Injection  of 
epinephrine  excites  glycogen olysis  in  the  liver  so  that  hyperglycemia 
and  glycosuria  become  established,  results  which  are  also  obtained  by 
stimulating  the  great  splanchnic  nerve.  Epinephrine  causes  the  clotting 
time  of  the  blood  discharged  from  the  liver  to  be  very  materially  short- 
ened, an  effect  also  produced  by  stimulating  the  splanchnic  nerve.63 

As  in  the  case  of  the  blood  vessels,  the  above  results  are  obtained  even 
after  the  sympathetic  nerves  to  the  part  have  been  allowed  to  undergo 
degeneration,  from  which  it  is  concluded  that  the  tissues  elaborate  some 


THE    END0CRIN1     ORGANS,    OR    DUCTLESS    GLANDS  737 

substance  which  reacts  with  epinephrine.  This  substance  may  be  pro- 
duced either  al  the  junction  between  the  nerve  and  muscle — the  myo- 
neural junction,  or  perhaps  throughout  the  protoplasm  itself.  It  is 
called  the  receptor  substance  of  Langley,  and  is  believed  to  react  nol 
only  with  epinephrine,  bu1  also  with  various  drugs.  The  receptor  sub- 
stance  Minis  to  increase,  if  not  in  amount,  at  leasl  in  sensitivity  after 
the  removal  of  the  nerve  conl  rol. 

Ergotoxin,  which  is  an  amine  obtained  from  ergol  and  also  from  cer- 
tain of  the  products  of  histidine,  has  an  action  on  the  receptor  substance 
which   is  inhibitory  and  therefore  antagonistic  to  that   of  epinephrine. 

The  antagonistic  action  of  ergotoxin  affects  the  excitatory  but  not 
the  inhibitory  actions  of  epinephrine.  By  using  this  drug  Ave  are  en- 
abled to  show  that,  although  the  main  effect  of  epinephrine  on  tissue  is 
excitatory,  a  less  marked  inhibitory  influence  may  be  simultaneously 
developed.  The  inhibitory  effect  may  also  sometimes  be  evoked  by 
doses  of  epinephrine  very  much  smaller  than  those  used  to  produce 
excitatory  effects.  These  faets  are  well  illustrated  in  the  case  of  the 
muscle  fiber  of  the  blood  vessels.  With  an  ordinary  dose  of  epinephrine 
constriction  occurs;  after  ergotoxin  the  same  dose  of  epinephrine  causes 
dilatation.  Or  this  latter  result  may  also  be  obtained  by  administer- 
ing to  a  normal  animal  quantities  of  epinephrine  that  are  very  much 
smaller  than  the  usual  quantity.  The  coexistence  of  inhibitory  and  ex- 
citatory influence  is  also  well  noted  in  the  case  of  the  uterus.  In  some 
animals  the  effect  of  epinephrine  on  this  organ  is  to  augment  its  rhythmic 
contractions,  in  others  to  inhibit  them.  In  the  former  case,  however,  if 
ergotoxin  is  first  of  all  administered,  epinephrine  in  its  usual  dosage  will 
invariably  produce  an  inhibitory  effect.  The  ergotoxin  no  doubt  acts  on 
the  receptor  substance,  and  similar  effects  have  also  been  produced  with 
apocodeine. 

Although  it  is  especially  on  plain  muscular  fiber  having  a  sympathetic 
nerve  supply  that  epinephrine  unfolds  its  action,  yet,  according  to  Can- 
non, it  increases  the  contracting  power  of  voluntary  muscle  and  dimin- 
ishes the  tendency  to  fatigue.* 


*For  further  details  of  these   effects   the  papers   of   Hoskins83  and  Ilartnian'14  should   be   consulted. 


CHAPTER  LXXXII 

THE  ADRENAL  GLANDS   (Cont'd) 
Variations  in  Physiologic  Activity 

Since  it  is  clearly  established  that  the  adrenal  glands  are  indispensable 
to  life  and  that  extracts  of  them  have  a  very  pronounced  physiologic  action, 
it  remains  to  consider  whether  the  glands  produce  this  internal  secre- 
tion within  the  body,  and  if  so,  whether  it  is  essential  for  the  well-being 
of  the  animal  or  required  only  under  certain  conditions.  We  must  also 
endeavor  to  find  out  upon  which  of  the  bodily  functions  of  the  intact 
animal  the  internal  secretion  acts.  These  problems  have  been  attacked 
by  three  methods  of  investigation:  (1)  by  comparing  the  epinephrine 
content  of  similarly  prepared  extracts  of  the  resting  gland  and  of  one 
removed  after  a  period  of  supposed  increased  activity;  (2)  by  collecting 
the  blood  as  it  flows  into  the  vena  cava  from  the  adrenal  vein  and  ex- 
amining it  for  epinephrine  by  physiologic  tests.  These  consist  in  observ- 
ing the  behavior  of  some  tissue  that  is  sensitive  to  the  action  of  epineph- 
rine, such  as  the  intestine  or  uterus,  after  applying  the  blood  or  serum 
to  it,  or  by  injecting  the  blood  or  serum  intravenously  into  another  ani- 
mal and  looking  for  epinephrine  effects;  and  (3)  by  allowing  the  blood 
of  the  adrenal  vein  to  be  discharged  under  certain  conditions  through 
the  vena  cava  into  the  blood  vessels  of  the  same  animal,  and  observing 
the  effect  produced  on  certain  physiologic  processes  which  in  one  way 
or  another  have  been  sensitized  toward  the  influence  of  epinephrine. 
This  autoinjection  method  has  recently  been  used  successfully  by  Stew- 
art and  Rogoff,66  their  favorite  structure  upon  which  to  observe  the 
epinephrine  effect  being  the  denervated  pupil. 

Assaying  the  Epinephrine  Content  of  the  Gland 

With  regard  to  the  first  mentioned  of  the  methods,  either  chemical  or 
physiologic  means  may  be  employed  to  assay  the  strength  of  the  ex- 
tracts. The  best  chemical  method  is  that  of  Cannon,  Folin  and  Denis,6- 
the  principle  of  which,  has  already  been  described.  The  physiologic 
method  yielding  most  satisfactory  results  is  that  of  Elliott,07  which  con- 
sists in  injecting  a  portion  of  the  extract  intravenously  into  animals 
from  which  the  influence  of  the  nerve  centers  on  the  heart  and  blood 
vessels  has  been  removed  by  decapitation.     The  rise  in  arterial  blood 

738 


THE    ADRENAL   GLANDS  ?:'.!• 

pressure  produced  by  the  injection  is  then  a  very  fair  measure  of  the 
amount  of  epinephrine  contained  in  it.  It  has  been  shown  thai  the  re- 
sults obtained  by  the  chemical  method  agree  very  closely  with  those  obtained 
by  the  physiologic,  hut  it  should  he  remarked  that  it  is  difficult  to  Bee  how  the 
physiologic  method  could  be  accurate  in  all  cases,  since  it  has  heen 
shown  that  with  greal  dilution  of  epinephrine  a  reversed  effect  a  vaso- 
dilatation— may  be  obtained.  Attempts  to  assay  the  strength  of  an 
epinephrine  solution  by  investigating  the  effects  which  it  produces  on 
other  preparations,  such  as  isolated  loops  of  intestine  or  uterus,  or  the 
enucleated  eyeball  of  the  frog-,  must  prove  unsuccessful,  since  the  effects 
are  by  no  means  dependent  on  the  concentration  of  epinephrine  in  the 
extract.  When  such  preparations  are  used  for  quantitative  purposes, 
the  strength  of  the  extract  must  he  judged  by  finding  the  extent  to 
which  it  can  be  diluted  and  still  remain  active. 

Quite  apart  from  the  foregoing  possible  sources  of  error,  it  must  he 
remembered  that  the  results  merely  give  us  an  idea  of  how  much  epineph- 
rine may  have  been  contained  in  the  gland  at  the  time  of  its  excision. 
They  can  not  tell  us  how  much  epinephrine  the  gland  was  secreting.  Prior 
to  excision  as  much  of  this  hormone  might  have  been  undergoing  a  process 
of  manufacture  in  the  gland  as  was  being  discharged  from  it,  so  that  the 
assayed  amount  would  represent  merely  the  balance  of  production  and  loss 
of  hormone  by  the  gland.  We  might  quite  well  find  that  the  amount  of 
epinephrine  in  the  excised  gland  was  normal  under  conditions  where 
there  had  been  an  excessive  discharge  of  it  into  the  blood;  that  is  to  say, 
loss  and  production  might  have  been  equal.  Where,  however,  a  marked 
deficiency  is  found  to  exist,  it  probably  indicates  that  exhaustion  of  the 
power  of  producing  epinephrine  was  taking  place. 

The  Epinephrine  Content  of  the  Blood. — The  second  method,  in  which 
blood  from  one  animal  is  tested  for  its  epinephrine  effect  by  intravenous 
injection  into  another  animal  or  by  applying  it  to  some  isolated  prepara- 
tion on  which  epinephrine  acts,  has  yielded  important  results.  Since 
serum  contains  all  the  epinephrine  of  blood,  it  can  be  conveniently  used 
for  the  tests  (Stewart  and  Rogoff).  The  isolated  physiologic  prepara- 
tions that  have  been  used  in  testing  for  epinephrine  in  the  animal  fluids 
are  as  follows: 

1.  A  segment  of  the  small  intestine  of  a  rabbit,  suspended  in  oxygen- 
ated Locke's  solution  at  body  temperature. 

2.  A  segment  of  the  uterus  of  a  nonpregnant  rabbit  similarly  prepared. 

The  apparatus  used  for  observing  the  contractions  of  either  prepara- 
tion consists  of  a  small  glass  chamber  furnished  below  with  a  hook  to 
which  one  end  of  the  segment  is  attached,  the  other  end  being  connected 


740 


THE    ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 


to  a  muscle  lever,  so  that  the  regular  rhythmic  contractions  can  be  regis- 
tered on  a  drum  (Fig.  190). 

Epinephrine  inhibits  the  contractions  of  the  intestine  but  stimulates 
those  of  the  uterus  of  most  animals,  the  intestine  preparation  being  the 
more  sensitive  (Fig.  191).  Indeed,  it  is  said  that  the  inhibition  in  this 
case  may  be  obtained  with  a  solution  containing  1  part  of  epinephrine  in 
20,000,000  of  solution.  In  using  this  method,  however,  great  care  and 
judgment  must  be  exercised  in  drawing  conclusions,  because  other  sub- 
stances present  in  the  blood  are  liable  to  affect  the  contractions;  thus, 


Air  vent 


Fig.    190. — Arrangement    of    apparatus  for    recording    contractions    of   a    uterine    strip,    intestinal 

strip,   or  ring,   etc.      The   metal   water-bath  is   made   of  a  cheap   metal   water-pail   with   a    heading   rod 

soldered  through   the   side  at  the   bottom.  A   short  metal   tube  is   soldered   into   a    1-inch   opening   in 

the  bottom  to  receive  a  perforated  cork  for  connecting  with  the  Harvard  muscle-warmer  inside. 
(From  Jackson.) 

certain  substances  in  blood  serum  which  have  been  produced  by  the  act 
of  blood  clotting  may  cause  augmentation  of  the  beat  in  both  the  intes- 
tinal and  the  uterine  preparations.  A  certain  amount  of  epinephrine  in 
Locke's  solution  is  consequently  more  likely  to  cause  inhibition  of  the 
intestine  than  a  similar  amount  added  to  blood  serum,  because  in  the  lat- 
ter case  the  pressor  substance  will  neutralize  the  depressor  effect  of  the 
epinephrine.  On  the  uterine  preparation,  both  the  blood  serum  and  the 
epinephrine  have  pressor  effects.  As  has  been  pointed  out  by  Gr.  N. 
Stewart,08  if  both  preparations  are  employed  for  testing  a  solution  sup- 


THE    ADRLXAL    GLANDS 


741 


posed  to  contain  epinephrine,  little  chance  of  error  is  likely  to  be  in- 
curred; that  is,  if  the  solution  produces  inhibition  of  the  intestine  along 
with  augmentation  of  the  uterus,  it  must  contain  epinephrine. 

3.  The  fresh  carotid  artery  of  the  sheep.     A  ring  cut  from  the  artery 
is  suspended  in  oxygenated  Locke's   solution   and   attached  below  to  a 


*«6^.ww««•W7%wr;A*''»*'*TO'*'t,,**;>^ 


*   LfgUCexsx&J. 


04JH**m$0 


/-/oooo 


Fig.  191. — Tracing  showing  the  effect  of  epinephrine  on  the  intestinal  contractions  and  on  the 
arterial  blood  pressure.  (The  preliminary  addition  of  barium  to  the  nutritive  fluid  may  be  disre- 
garded.)      (From    Jackson.) 

small  hook  and  above  to  a  light  muscle  lever,  by  which  the  contraction 
of  the  muscle  fibers  can  be  observed.  Epinephrine  causes  the  muscle  to 
contract,  but  the  test  is  not  so  sensitive  as  the  foregoing,  especially  in 
the  presence  of  blood  serum,  because  the  pressor  substances  therein  con- 
tained also  cause  contraction.  Blood  plasma  does  not  contain  the  pres- 
sor substances,  so  that  oxalated  plasma  should  be  used  in  place  of  serum 


742 


THE    ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 


in  applying  the  test.     To  increase  the  sensitiveness  of  the  muscle,  the 
artery  ring  should  be  slightly  stretched  by  loading  the  lever. 
4.  The  blood  vessels  of  a  fro</.    This  method  depends  on  the  same  prin- 


Fig.    192. — Arrangement    of    apparatus    for    perfusion    of    the    vessels    of    a    brainless    frog.       (From 

Jackson.) 

ciple  as  in  that  just  described.  The  fluid  supposed  to  contain  epinephrine 
is  added  to  Locke's  solution,  which  is  meanwhile  being  perfused  under 
constant  pressure   through   the  blood   vessels   and  the   rate    of  outflow 


THE   ADRENAL   GLANDS  743 

noted  (Fig.  192).  If  the  fluid  added  to  the  inflowing  fluid  contains  epi- 
nephrine, the  outflow  will  become  diminished.  This  is  a  very  satisfactory 
method,  although  it  is  somewhat  limited  in  scope  unless  large  frogs  are 
procurable,  because  of  the  difficulty  of  getting  the  necessary  cannula? 
into  the  vessels  (aorta  and  abdominal  vein). 

5.  The  pupil  of  the  enucleated  eye  of  the  frog.  Extremely  small  traces 
of  epinephrine  are  observed  to  cause  a  dilatation. 

6.  The  denervated  iris.  The  fluid  to  be  tested  is  placed  in  the  conjunc- 
tival sac  of  an  animal  from  which  the  superior  cervical  ganglion  of  the 
corresponding  side  has  been  removed  some  days  previously.  Under  such 
conditions,  if  epinephrine  is  present  in  the  fluid,  dilatation  of  the  pupil 
occurs.     Both  of  the  preceding  reactions  we  owe  to  Meltzer.70 

It  should  be  emphasized  that,  although  each  of  these  methods  is  in 
itself  very  sensitive  for  the  detection  of  epinephrine  without  being  al- 
ways  specific,  yet  the  result  should  not  be  considered  conclusive  unless 
definite  effects  have  been  secured  by  at  least  two  methods  that  are  as 
far  as  possible  independent  of  each  other. 

As  an  outcome  of  investigations  by  these  methods  it  has  been  found 
that,  when  blood  from  the  adrenal  vein  is  collected  in  a  pocket  of  vena 
cava  made  by  applying  clamps  above  and  below  the  entrance  of  the 
adrenal  veins,  the  presence  of  epinephrine  can  be  revealed,  the  rate  of 
secretion  being  from  0.0003  to  0.001  mg.  per  kilogram  of  body  weight 
per  minute  (Stewart  and  Rogoff).  The  absolute  amount  of  epinephrine 
liberated  from  the  gland  can  be  measured  only  by  finding  the  concen- 
tration in  the  adrenal  vein  blood  and  the  rate  of  bloodflow.  This  amount 
is  approximately  constant,  so  that  the  concentration  in  the  blood  which 
collects  in  the  cava  pocket  varies  inversely  with  the  rate  of  bloodflow. 
In  asphyxia  the  bloodflow  is  decreased  so  that  the  concentration  of  epi- 
nephrine increases,  but  there  is  no  change  in  the  absolute  amount.  Nei- 
ther anesthesia  nor  trauma  affects  the  amount.  The  concentration  is 
likely  to  rise  late  in  an  experiment  because  of  the  slowing  of  bloodflow. 
Adrenal  activity  may,  however,  be  excited  by  massage  of  the  gland,  or 
by  stimulation  of  its  nerve  supply  through  the  great  splanchnic  nerve. 
The  presence  of  epinephrine  in  blood  collected  directly  from  the  adrenal 
veins  does  not  justify  us  in  concluding  that,  when  mixed  with  the  re- 
mainder of  the  blood  in  the  body,  there  would  be  a  sufficient  concentra- 
tion of  this  substance  to  develop  any  of  its  activities.  It  has  therefore 
been  necessary  to  devise  methods  by  which  this  possibility  could  be 
tested. 

The  Autoinjection  Method.— Such  a  method  was  first  of  all  success- 
fully used  by  Asher,  who  employed  an  animal  from  which  all  the  abdom- 
inal viscera  had  been  removed.     On  stimulation  of  the  great  splanchnic 


744  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

nerve  a  rise  in  arterial  blood  pressure  occurred  provided  the  adrenal 
veins  were  open,  but  not  so  if  the  adrenal  veins  were  clamped.  By  re- 
moving the  viscera,  the  effect  of  splanchnic  stimulation  on  the  abdom- 
inal blood  vessels  themselves  is  eliminated,  and  any  constriction  which 
occurs  in  the  blood  vessels  of  the  rest  of  the  body  must  obviously  be  due 
to  the  action  of  epinephrine. 

The  most  satisfactory  of  these  methods  is  that  more  recently  employed 
by  Stewart,  Rogoff  and  Gibson,09  which  consists  in  observing  the  be- 
havior of  the  pupil  on  the  side  from  which  the  superior  cervical  ganglion 
has  been  removed  about  one  Aveek  previously.  Of  course  the  blood  pres- 
sure effect  is  also  observed. 

Among  the  most  important  results  secured  by  this  method  it  may  be 
mentioned  that  dilatation  of  the  pupil  occurs  on  stimulation  of  the  great 
splanchnic  nerve,  provided  the  vena  cava  and  adrenal  vein  are  unobstructed 
so  that  the  blood  from  the  adrenal  glands  can  get  to  the  head.  If  the  vena 
caA*a  is  clamped  and  the  splanchnic  nerve  stimulated,  there  is  no  pupil- 
lary dilatation,  but  it  immediately  occurs  after  the  clamp  is  removed. 
Epinephrine  continues  to  be  discharged  for  a  considerable  period  of  time 
after  stimulating  the  splanchnic  nerve,  but  the  immediate  increase  Avhich 
folloAvs  the  application  of  the  stimulus  does  not  last  long,  so  that  more 
secretion  can  be  obtained  by  intermittent  than  by  continuous  stimula- 
tion. It  does  not  seem  to  be  possible  to  exhaust  the  adrenal  gland  of  its 
supply  of  active  material  by  stimulating  the  splanchnic — a  fact  which 
would  seem  to  throw  considerable  doubt  on  the  reliability  of  the  con- 
clusions arrived  at  by  the  use  of  those  methods  in  which  extracts  of  the 
gland  are  assayed  (see  page  739).* 

Many  interesting  facts  concerning  the  nature  of  the  innervation  of  the 
gland  have  been  secured  by  one  or  other  of  the  aboAre  methods.  "After 
section  of  the  sympathetic  chain  and  the  great  splanchnic  nerves  on  both 
sides  (in  the  thorax),  no  epinephrine  is  secreted  into  the  blood  of  the 
adrenal  vein,  and  Avhen  one  gland  is  extirpated  and  the  nerve  connec- 
tions of  the  other  entirely  cut,  the  epinephrine  content  of  the  adrenal 
A'ein  blood  sinks  to  not  more  than  1/1000  of  the  normal  amount.  The 
animals  survive  this  latter  operation  and  behave  in  a  perfectly  normal 
fashion,  indicating  that  the  internal  secretion  of  the  adrenals  can  not  have 
the  physiologic  significance  so  often  ascribed  to  it. 

The  splanchnic  fibers  concerned  in  the  secretion  of  epinephrine  seem 
to  come  from  a  nerve  center  situated  relatively  low  down  in  the  spinal 
cord.  Section  of  the  cord  at  the  level  of  the  last  cervical  segment  does 
not  affect  the  spontaneous  secretion,  but  this  disappears  Avhen  the  section 
is  made  below  the  third  thoracic  segment.       (SteAvart  and  Rogoff.) 


*  Another  great   advantage   of   t1>e   aul'omjection    method    is    that    no   confusion    can    lie   causcl    by 
♦  lie  development  of  pressor  substances  through   clotting. 


THE   ADRENAL   GLANDS  745 

lu  connection  with  these  observations  it  is  of  interest  to  note  that  dur- 
ing stimulation  of  the  splanchnic  nerve  in  a  normal  animal,  the  conse- 
quent rise  in  blood  pressure  shows  two  peaks  (see  Fig.  2'.),  page  L37).  The 
first  is  no  doubt  due  to  direct  stimulation  of  the  splanchnic  vasoconstric- 
tors, and  the  second  to  the  outpouring  of  epinephrine  into  the  blood,  the 
justification  for  this  conclusion  being  that  the  latter  rise  fails  to  appear 
after  removal  of  the  adrenal  glands. 

Taking  the  results  as  a  whole,  it  is  indeed  doubtful  whether  under  nor- 
mal conditions  a  sufficient  amount  of  epinephrine  is  discharged  into  the 
blood  of  the  vena  cava  to  affect  appreciably  the  tone  of  the  blood  vessels, 
and  this  conclusion  seems  all  the  more  justified  because  of  the  fact  that 
small  quantities  of  epinephrine  have  a  dilating  rather  than  a  constricting 
influence,  ;it  least  on  certain  vessels  (Hartman*4).  It  may  be,  however,  that 
the  maintenance  of  vascular  tone  under  certain  conditions  is  greatly  as- 
sisted by  the  presence  of  epinephrine  in  the  blood.  Similarly  the  sympa- 
thetic control  of  other  functions  may  be  facilitated  by  the  presence  of 
small  amounts.  It  has  been  found,  for  example,  that,  although  stimula- 
tion of  the  celiac  plexus  causes  the  glycogen  stored  in  the  liver  to  be  con- 
verted into  sugar,  this  result  is  not  as  a  rule  obtained  on  stimulating 
plexus  shortly  after  removal  of  the  adrenal  glands.  The  presence 
of  epinephrine  in  the  blood  would,  therefore,  seem  to  be  necessary  to  bring 
about  functional  activity  of  the  sympathetic  nerve  endings  concerned  in 
the  glycogenolytic  process  (see  page  637). 

Adrenalemia. — In  the  light  of  these  researches  it  is  important  to  point 
out  that  a  great  part  of  the  work  done  by  clinical  observers  purporting  to 
show  that  in  such  conditions  as  nephritis  and  arteriosclerosis  there  is  an 
increase  of  epinephrine  in  the  blood,  has  been  found  by  Stewart  and 
others,  using  controlled  methods,  to  be  entirely  unproven.70  Some  inves- 
tigators, however,  still  hold  that  temporary  conditions,  such  as  transient 
rises  of  arterial  blood  pressure  or  temporary  glycosuria,  may  sometimes  be 
due  to  increased  adrenal  discharge  into  the  blood. 

Epinephrine  has  been  thought  to  be  a  substance  which  is  secreted  into 
the  blood  in  supernormal  amount  when  certain  emergencies  arise,  the  most 
important  of  these  being  fright,  or  some  other  extreme  emotion.  This 
belief  has  arisen  partly  from  the  similarity  between  the  general  behavior 
of  an  animal  following  the  intravenous  injection  of  epinephrine  and  dur- 
ing states  of  extreme  excitement.  Dilatation  of  the  pupils,  bristling  of 
the  hair,  salivation,  rise  in  arterial  blood  pressure,  inhibition  of  the  intes- 
tinal movements,  protrusion  of  the  eyeballs  are  all  symptoms  of  fear  just 
as  they  are  of  epinephrine  injection.  Impressed  by  these  resemblances 
Cannon72  undertook  an  extended  research  to  test  the  hypothesis  that  the 
reaction  of  an  animal  to  tear  and  other  emotional  states  is  dependent  on 


746  THE    ENDOCRINE    ORGANS,    OR   DUCTLESS    GLANDS 

hypersecretion  of  epinephrine  into  the  blood.  The  results  seemed  to  con- 
firm the  hypothesis.  In  the  first  place,  it  was  found  that,  whereas  the  blood 
drawn  from  the  vena  cava  opposite  the  entry  of  the  adrenal  veins  (by 
passing  a  catheter  up  the  femoral  vein  till  its  free  end  lay  at  this  level)  in 
a  normal  male  eat  did  not  give  evidence  of  the  presence  of  epinephrine 
when  tested  by  means  of  the  intestinal  segment  method,  it  did  so  in  a 
cat  that  had  previously  been  frightened  by  allowing  a  dog  to  bark  at  it. 
Such  results  were  not  obtained  after  removal  of  the  adrenal  gland,  or  in 
a  female  cat,  which  is  usually  indifferent  to  such  a  method  of  frightening. 
Cannon  also  thought  that  many  of  the  other  adaptations  which  take  place 
in  an  animal  in  this  condition  could  be  attributed  to  the  presence  of  an 
excess  of  epinephrine  in  the  blood.  The  three  most  important  of  these 
are:  (1)  increased  discharge  of  sugar  from  the  liver  into  the  blood;  (2)  in- 
creased efficiency  of  muscular  contraction;  (3)  diminished  clotting  time  of 
the  blood — all  of  which  are  adaptations  enabling  the  animal  either  to  con- 
quer the  source  of  the  fear  or  to  be  in  a  better  position  to  recover  from 
any  bodily  injury  involving  a  loss  of  blood  should  he  suffer  bodily  dam- 
age. Stewart  and  Eogoff  have  more  recently  thrown  considerable  doubt 
on  these  conclusions  by  finding  that  cats  in  which  both  adrenal  glands  are 
entirely  removed  from  the  influence  of  the  nervous  system,  behave  like 
normal  animals  when  frightened,  and  develop  hyperglycemia  when  as- 
phyxiated or  etherized.  It  is  scarcely  necessary  to  point  out  that,  until 
it  is  definitely  established  by  experimental  investigation  that  epinephrine 
may  be  discharged  in  excessive  amounts  under  certain  conditions,  it  is 
irrational  to  assume  that  such  may  occur  in  disease.  The  surgical  removal 
of  the  adrenal  gland  is  certainly  not  warranted  under  any  circumstances. 

The  Association  of  the  Adrenal  with  Other  Endocrine  Organs 

We  have  at  present  very  little  accurate  and  reliable  information  on  the 
association  of  the  adrenal  with  other  endocrine  organs.  That  epinephrine 
has  an  influence  on  many  diverse  organs  and  glands  is  an  undoubted 
fact,  but  this  is  more  probably  to  be  attributed  to  an  activating  influence 
on  sympathetic  nerve  endings  than  to  any  specific  relationship  between 
the  adrenal  glands  and  the  gland  in  question.  The  most  important  of  the 
results  that  have  been  obtained  are  the  following: 

1.  With  the  Thyroid  and  Parathyroid.— Cannon  and  Cattell,  after  con- 
firming Bradford's  discovery  that  an  electric  current  of  action  is  set  up  in 
the  salivary  gland  when  it  is  excited  to  activtiy,  proceeded  to  investigate 
the  occurrence  of  such  a  current  in  the  thyroid  gland.73  By  placing  one 
nonpolarizable  electrode  on  the  gland  itself  and  the  other  on  the  neigh- 
boring subcutaneous  tissues  or  on  the  trachea,  a  current  was  found  to  be 
set  up  by  stimulation  of  the  sympathetic  nerve  supply  of  the  thyroid,  by 
intravenous  injection   of   epinephrine,    or   by   stimulation   of  the    great 


TIIIC  ADRENAL  GLANDS  747 

splanchnic  nerve  before  it  reaches  the  adrenal  gland.  This  last  result, 
which  is  the  most  important  in  the  present  connection,  was,  however,  not 
observed  when  the  blood  of  the  inferior  vena  cava  was  prevented  by  the 
application  of  a  clamp  from  getting  to  the  heart,  but  immediately  ap- 
peared,  after  stimulation,  when  the  clamp  was  removed.  This  experiment 
taken  alone  does  not,  however,  justify  the  conclusion  that  there  is  any 
direct  relationship  between  the  adrenal  glands  and  the  thyroid,  because 
there  are  in  the  thyroid  gland  structures  such  as  the  muscle  fibers  in  the 
blood  vessels,  which  a  hypersecretion  of  epinephrine  might  affect.  Before 
any  direct  relationship  between  the  two  glands  could  be  claimed  to  exist, 
it  would  be  necessary  to  show  that  the  thyroid  action  current  is  obtained 
with  a  concentration  of  epinephrine  in  the  blood  lower  than  that  affecting 
the  blood  vessels. 

2.  With  the  Sexual  Glands. — As  mentioned  above,  a  very  direct  rela- 
tionship exists  between  the  development  of  the  sexual  glands  and  that  of 
the  suprarenals,  particularly  the  cortex  of  the  glands.  In  addition  to  the 
evidence  above  furnished,  it  may  be  mentioned  that  in  hyperplasia  of  the 
adrenals  changes  occur  in  the  testicles,  particularly  in  their  interstitial 
cells. 

3.  With  -the  Liver. — Of  the  many  functions  of  this  gland  that  which  is 
most  directly  associated  with  epinephrine  is  the  production  of  glucose 
from  glycogen — the  glycogenolytic  process  (see  page  669).  The  injection 
of  epinephrine  causes  an  immediate  discharge  of  such  an  excess  of  glucose 
into  the  blood  that  hyperglycemia  and  glycosuria  immediately  follow. 
This  result  is  most  striking  when  the  injection  is  made  in  glyco gen-rich 
animals.  In  animals  from  which  all  the  glycogen  of  the  liver  has  been 
removed  by  starvation,  the  injection  of  large  amounts  of  epinephrine 
causes  glycogen  to  accumulate  in  the  liver  cells — a  result  which  it  is 
difficult  to  interpret. 

In  the  light  of  the  fact  that  stimulation  of  the  great  splanchnic  nerve 
causes  a  demonstrable  increase  of  epinephrine  in  the  blood,  a  natural  con- 
clusion is  that  the  glycosuria  and  hyperglycemia  which  are  known  to  re- 
sult from  stimulation  of  the  splanchnic  nerve  or  of  its  center  in  the 
medulla,  must  be  dependent  upon  a  hypersecretion  of  epinephrine. 
Evidence  supporting  this  hypothesis  seemed  to  be  furnished  by  the  obser- 
vation that,  after  the  removal  of  the  adrenal  glands,  stimulation  of  the 
splanchnic  or  of  the  so-called  "diabetic"  center  in  the  fourth  ventricle 
no  longer  produced  glycosuria  even  in  a  glycogen-rich  animal.  But  it  is 
difficult  to  see  how  such  an  important  physiologic  process  as  that  of  the 
nerve  control  of  the  production  of  sugar  by  the  liver  should  be  dependent 
on  the  hypersecretion  of  the  adrenal  gland,  especially  since  the  epineph- 
rine would  have  to  be  carried  by  the  blood  around  a  considerable  part  of 


748  THE    ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 

the  circulation  before  it  arrived  at  the  place  on  which  it  is  to  act.  More- 
over, it  has  been  shown  that  stimulation  of  the  previously  cut  hepatic 
nerve  plexus  (around  the  hepatic  pedicle)  in  a  normal  animal  produces 
hyperglycogenolysis,  in  which  case  there  can  be  no  question  of  a  hyper- 
secretion of  epinephrine. 

No  doubt  the  adrenal  glands  have  some  important  relationship  to  the 
nerve  control  of  the  glycogenolytic  process,  for,  in  animals  from  which  the 
adrenal  glands  have  been  removed,  stimulation  of  the  hepatic  plexus  does 
not  produce  hyperglycemia.  From  this  result  it  "would  appear  that  the 
presence  of  a  certain  amount  of  epinephrine  in  the  blood  is  necessary  for 
the  proper  transmission  of  the  nerve  impulse  from  the  sympathetic  nerve 
fibers  to  the  liver  cell.  When  the  nervous  system  is  stimulated  in  such 
a  Avay  as  to  excite  the  glycogenolytic  process,  two  effects  both  operat- 
ing in  the  same  direction  with  regard  to  the  glycogenic  function  are 
developed:  the  one,  a  hypersecretion  of  epinephrine,  which  activates 
the  sympathetic  nerve  endings,  the  other,  the  transmission  of  the  nerve 
impulse  to  the  liver  cell  (Maeleod  and  R.  (I.  Pearce).71 

4.  With  the  Pancreas. — The  function  of  the  pancreas  here  concerned 
is  that  of  its  supposed  internal  secretion  from  the  Isles  of  Langerhans. 
Since  epinephrine  readily  produces  glycosuria,  and  since  excision  of 
the  pancreas  has  the  same  effect,  it  has  been  natural  to  inquire  whether 
any  relationship  exists  between  the  two  glands,  and  some  observers 
have  obtained  results  which  they  interpret  as  indicating  that  it  does. 
Certain  observers  even  state  that  glycosuria  does  not  occur  after  the 
injection  if  at  the  same  time  extract  of  pancreas  is  injected.  It  is  al- 
most certain,  however,  that  these  results  are  not  trustworthy.  Thus, 
removal  of  the  adrenal  glands  in  an  animal  suffering  from  pancreatic 
diabetes  does  not  restore  any  of  the  lost  power  of  utilizing  glucose 
during  the  few  hours  that  the  animal  remains  alive.71  That  some  rela- 
tionship may,  however,  exist  is  indicated  by  the  fact  that  epinephrine 
causes  dilatation  of  the  pupil  when  it  is  dropped  into  the  eye  of  a  per- 
son suffering  from  diabetes,  whereas  it  has  no  such  effect  in  the  normal 
individual. 


CHAPTER   LXXXIH 
THE  THYROID  AND  PARATHYROID  GLANDS 

Structural  Relationships 

The  thyroid  and  parathyroid  glands  are  intimately  associated,  anatom- 
ically, in  most  animals.  The  thyroid  is  present  in  all  the  vertebrates, 
but  the  parathyroids  do  not  occur  below  the  amphibia.  The  thyroid 
exists  as  two  lateral  lobes  joined  over  the  trachea  by  the  so-called  isthmus. 
The  parathyroids  are  very  much  smaller,  being  four  in  number  and 
located  in  pairs  on  the  posterior  aspect  of  the  thyroid  lobes.  The  two  upper 
parathyroids  are  usually  more  or  less-  embedded  in  the  thyroid  tissue, 
whereas  the  lower  ones  are  much  more  loosely  attached  to  the  thyroid; 
indeed,  in  some  animals  they  are  quite  separate  from  it  and  may  be 
located  at  a  distance,  as  in  the  mediastinum.  Accessory  thyroid  and 
parathyroid  glands  are  sometimes  present  in  the  tissues  of  the  neck,  or 
in  the  anterior  mediastinum,  accessory  parathyroids  being  common  in 
the  rabbit  and  rat,  and  parathyroid  tissue  being  present  in  the  thymus 
in  5  per  cent  of  dogs  (.Marine7').  Before  these  anatomic  relationships 
Were  thoroughly  worked  out,  there  was  much  confusion  in  the  interpre- 
tation of  the  results  following  removal  of  one  or  the  other  gland. 

In  their  histologic  structure  and  embryologic  derivation,  the  two- 
glands  are  very  different.  The  parathyroids  are  developed  as  an  out- 
growth from  the  third  and  fourth  branchial  pouches,  and  they  are  com- 
posed of  masses  of  epithelial-like  cells,  sometimes  more  or  less  divided 
up  into  lobules  or  trabecular  by  bands  of  connective  tissue.  The  cells 
contain  granules,  some  of  which  are  of  a  fatty  nature.  Sometimes  col- 
loid-like material  is  found  between  the  cells,  or  it  may  be  enclosed  in 
small  vesicles  not  unlike  those  of  the  thyroid,  although  usually  consider- 
ably smaller.  The  blood  vessels  are  extremely  numerous,  and  form 
sinus-like  capillaries,  which  come  into  close  relationship  with  the  epi- 
thelial cells  of  the  glands.  Nerves  also  are  abundant  and  pass  both  to 
the  vessels  and  to  the  secreting  cells.  The  blood  vessels  are  derived  from 
the  inferior  thyroid  artery. 

The  thyroid  is  developed  by  immediate  outgrowth  from  the  entoderm 
lining  the  floor  of  the  pharynx,  at  a  level  between  the  first  and  second 
branchial  pouches.  Represented  at  first  by  a  solid  column  of  cells, 
there  very  soon  occurs  a  division  at  the  lower  end  into  two  lateral  por- 

749 


750  THE   ENDOCRINE   ORGANS,    OR    DUCTLESS    GLANDS 

tions,  and  the  original  solid  column  becomes  hollowed  out.  The  two 
lateral  branches  of  the  original  column  divide  again  and  again  so  as  to 
form  a  system  of  hollow  tubes  lined  with  epithelium.  These  afterward 
become  cut  up  so  as  to  form  the  closed  vesicles  characteristic  of  the 
gland.  Each  vesicle  is  more  or  less  spheroidal  in  shape,  and  has  no 
basement  membrane,  but  its  walls  are  formed  by  a  layer  of  epithelial 
cells,  which  may  be  columnar,  cubical,  or  flattened  in  shape.  Each  vesicle 
is  filled  with  the  so-called  colloid  material,  which  is  peculiar  in  con- 
taining iodine,  and  between  the  vesicles  is  a  layer  of  connective  tissue 
often  containing  small  cells,  some  of  which  are  not  unlike  those  of  the 
parathyroid.  The  connective  tissue  also  contains  the  blood  vessels, 
which  are  very  numerous — indeed,  the  thyroid,  in  proportion  to  its  size, 
receives  more  than  five  times  as  much  blood  as  the  kidneys,  the  only 
tissue  that  surpasses  it  in  this  regard  being  the  medulla  of  the  adrenal 
gland  (see  page  211).  The  nerves  arise  from  both  the  vagus  and  the 
sympathetic  systems  and  have  been  traced  to  the  secreting  epithelial 
cells.    The  above  description  applies  to  a  strictly  normal  gland. 

THE  THYROID  GLAND 

Condition  of  the  Gland 

In  the  crowded  communities  of  the  Great  Lakes  Basin  of  this  conti- 
nent, it  has  been  found  that  in  most  animals  the  thyroid  gland  is  more  or 
less  abnormal.  In  Cleveland,  for  example,  Marine  has  found  this  to  be 
the  case  in  well  over  90  per  cent  of  the  dogs  brought  to  the  laboratory.77 
The  condition  usually  goes  under  the  name  of  simple  goiter,  which  in- 
cludes all  thyroid  enlargements  except  those  of  exophthalmic  goiter. 
In  man  the  goiter  originates  usually  about  the  age  of  adolescence  and 
more  frequently  in  girls  than  in  boys.  It  may  sometimes  pass  over  into 
the  exophthalmic  type.  The  exact  pathologic  changes  in  the  goitrous 
gland  vary  with  the  species  of  animal  and  with  the  duration  of  the  dis- 
ease. In  man,  besides  the  cystic  or  colloid  goiter  an  adenomatous  type 
is  very  common  although  rare  in  other  animals. 

From  the  numerous  observations  that  have  been  made  on  the  glands  of. 
domestic  animals,  it  has  been  clearly  established  that  the  very  earliest 
sign  of  goiter  is  a  diminution  in  the  iodine  content  of  the  gland;  fol- 
lowed by  an  increase  in  the  epithelial  cells  and  in  the  blood  supply  and  a 
decrease  in  the  colloid.  Such  hyperplasia  may  be  induced  in  what  re- 
mains after  removal  of  a  large  part  of  a  normal  gland  (compensatory 
hyperplasia),  or  if  a  similar  operation  be  performed  early  in  pregnancy, 
the  young  when  born  will  be  found  to  have  hyperplastic  thyroids.  A 
certain  degree  of  hyperplasia  exists  as  an  accompaniment  of  pregnancy, 


i  ill     THYROID    \.\l>    PARATHYROID   GLANDS  75] 

and  it  can  be  produced  in  normal  animals  (particularly  rats)  by  placing 
them  on  an  excessive  meal  diet.  Important  observations  bearing  on  this 
point  have  been  made  by  .Marine  on  brook  trout,  ill  which  it  lias  been 
found  that  the  so-called  carcinoma  that  develops  when  the  fish  kept  in 
hatcheries  arc  fed  with  unsuitable  food  and  overcrowded,  is  really  a 
typical  hyperplasia.    In  its  second  stage  Ibis  develops  into  what  is  known 


Fig.    193. — Microphotographs    of    thyroid    gland    of    dog.      A,    normal    hyperplasia;    B,    active    hyper- 
plasia;   C,   colloid   goiter.      (From    Marine    and    Lenhart.) 

as  colloid  goiter  which  is  produced  by  a  deposition  of  colloid  material 
between  the  rows  of  cells  so  as  to  cause  an  opening  out  again  of  the 
vesicles  (Fig.  193).,  with  a  consequent  tendency  to  a  reversion  to  the 
normal  histologic  structure,  so  far  as  this  is  possible.  The  vesicles  in 
such  a  gland  are  of  enormous  size,  and  the  lining  epithelium,  low  cubical, 
or  almost  flat  in  shape. 

The  outstanding  characteristic  feature  of  the  colloid  material  is  that 


752  THE    END0CRIN]     ORGANS,    OR    DUCTLESS    GLANDS 

it  contains  iodine,  which  exists  in  combination  with  a  nonprotein  nitrog- 
enous base,  ami  is  usually  called  iodothyrin.  In  the  gland  itself  the 
iodothyrin  may  be  in  combination  with  protein,  forming  iodothyro- 
globnlin.  E.  C.  Kendall79  has  recently  succeeded  in  isolating  a  pure 
crystalline  substance  of  perfectly  constant  composition  and  containing 
over  60  per  cent  of  iodine.  It  is  called  alpha-iodine,  and  has  been  identi- 
fied as  an  indole  compound.  In  extremely  minute  dosage  it  greatly  affects 
the  energy  metabolism,  and  is  said  to  induce  symptoms  like  exophthalmic- 
goiter.  Its  therapeutic  value  in  cases  of  thyroid  deficiency  is  remarkable. 
Kendall  believes  this  substance  to  be  the  active  constituent  of  the  thyroid 
and  to  be  associated  with  the  metabolism  of  amino  acids.  For  one  thing, 
when  it  is  given  alone  no  change  occurs  in  pulse  rate,  whereas  if  amino 
acids  are  given  along  with  it,  there  is  acceleration. 

The  importance  of  the  relationship  between  the  function  of  the  thyroid 
and  the  iodine-containing  material  is  indicated  by  the  changes  which 
occur  in  the  percentage  of  iodine  in  the  glands  under  varying  condi- 
tions of  activity.  Marine  observed  that  the  amount  of  iodine  is  inversely 
proportional  to  the  degree  of  hyperplasia  of  the  gland,  and  when  the 
hyperplastic  condition  becomes  fully  developed,  scarcely  a  trace  of 
iodine  is  contained  in  the  gland.  Later,  when  the  hyperplasia  gives 
place  to  colloid  goiter,  the  iodine  increases  again,  both  absolutely  and 
relatively.  Moreover,  it  has  been  found  that  if  iodide  be  administered 
to  an  animal  suffering  from  hyperplasia,  the  hyperplastic  condition  very 
quickly  disappears  fFig.  192)  and  the  animal  becomes  normal.  Thus,  in 
brook  trout,  the  poor  nutritive  condition  of  the  fish  when  hyperplasia  has 
developed  can  be  immediately  remedied  by  placing  them  in  larger  quan- 
tities of  ninning  water  or  by  adding  small  traces  of  iodide  to  the  water. 
The  .administration  of  small  amounts  of  iodine  as  in  ordinary  salt  from 
salt  deposits  also  prevents  goiter  in  farm  stock,  this  having  been  first 
noted  in  the  State  of  Michigan,  where  prior  to  the  discovery  of  salt 
deposits  sheep  breeding  was  an  entire  failure.  The  importance  of  admin- 
istering small  doses  of  iodides  to  school  children  living  in  goitrous  dis- 
tricts has  recently  been  emphasized  by  Marine  and  Kimball.78  As  small 
a  dose  as  0.001  gm.  at  weekly  intervals  prevents  goiter  in  puppies  sus- 
ceptible to  it. 

Experimental  Thyroidectomy 

A  correct  interpretation  of  the  functional  changes  and  symptoms  which 
follow  upon  partial  or  complete  removal  of  the  thyroid  gland,  or  from 
its  disease,  has  proved  a  very  difficult  problem,  partly  because  sufficient 
care  has  not  been  taken  to  note  how  much  parathyroid  tissue  was  re- 
moved along  with  the  thyroid,  and  partly  because  the  fact  has  been  over- 


Mil     THYROID    AND    PARATHYROID   GLANDS  753 

looked  thai  the  effects  produced  bj  thyroidectomy  and  parathyroid- 
ectomy are  often  very  differenl  in  animals  of  the  same  kind  a1  dif- 
ferent ages.  Speaking  generally,  it  may  be  said  thai  the  influence  of  the 
parathj  roid  is  focused  mainly  on  the  nerve  centers  and  only  to  a  second- 
ary degree  on  the  metabolic  functions,  whereas  the  reverse  is  the  case 
with  the  thyroid,  its  main  effed  being  on  metabolism,  although  i1  prob- 
ably also  exercises  a  secondary  effed  on  the  aerve  centers.  More  so 
than  in  the  case  of  any  oilier  endocrine  organ,  our  knowledge  concerning 
the  function  of  the  thyroid  has  been  gained  by  clinical  experience,  and 
it  is  difficult  to  say  whether  the  clinical  or  the  experimental  method  has 
contributed  the  greater  amount  of  information. 

The  results  of  experimental  extirpation  of  the  thyroid  vary  accord- 
ing to  the  age  of  the  animal,  and  frequently  they  are  by  no  means 
marked,  provided  sufficient  parathyroid  tissue  has  been  undamaged. 
The  symptoms  are  in  general  thickening  and  drying  of  the  skin,  with  a 
tendency  to  adiposity  and  a  loss  of  tone  of  the  muscle.  The  body  tem- 
perature is  low  and  the  sexual  functions  hecome  subnormal.  Nervous 
symptoms  in  the  direction  of  mental  dullness  and  lethargy  are  also 
usually  present.  Surgical  removal  of  the  thyroid  in  man  produces  the 
condition  known  as  cachexia  strumipriva.  The  symptoms  may  first  of 
all  hecome  apparent  a  few  days  after  the  operation,  or  they  may  remain 
latent  for  years,  and  then  develop  so  as  to  produce  the  condition  known 
as  myxedema.  "When  nervous  symptoms  are  prominent  in  cachexia 
strumipriva,  it  is  usually  taken  as  evidence  that  an  excessive  amount 
of  parathyroid  tissue  has  been  destroyed.  Kocher  states  that  after  com- 
plete loss  of  the  thyroid,  life  is  impossible  for  more  than  seven  years, 
and  that  to  prevent  ultimate  ill  effects,  at  least  one-fourth  of  the  organ 
should  be  left  intact. 

Disease  of  the  Thyroid 

The  symptoms  of  diseased  conditions  of  the  thyroid  may  he  inter- 
preted as  the  consequence  of  increased  or  diminished  functioning  of  the 
gland.  Sometimes,  however,  the  less  active  gland  is  really  increased  in 
hulk,  this  increase  being  caused  by  the  accumulation  in  it  of  very  large 
quantities  of  colloid  material  accompanied  by  an  attenuated  condition 
of  the  vesicular  cells  (see  page  751).  When  the  "land  is  atrophied  at 
birth,  the  condition  of  cretinism  soon  becomes  developed  (Fig.  194).  The 
characteristic  features  of  cretinism  are:  (1)  An  arrest  of  growth,  espe- 
cially of  the  skeleton,  accompanied  by  incomplete  ossification  of  the  long 
bones  and  failure  of  the  fontanelles  of  the  skull  to  close  properly.  (2) 
Poor  development  of  the  muscular  system.  |  3)  An  unhealthy,  dry.  swollen 
condition  of  the  skin,  so  that  it  is  yellowish  in  color,  the  face  being  pale 


754 


T1IK    ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 


and  puffy.  (4)  An  abnormal  development  of  the  connective  tissues 
causing  a  shapeless  condition  of  the  surface;  the  abdomen  is  always 
swollen,  the  hands  and  feet  are  shapeless,  and  the  nose  depressed.  (5) 
The  nervous  system  also  fails  to  develop  properly,  so  that  at  the  age  of 
puberty  or  over,  the  child  remains  like  an  infant  in  his  mental  behavior, 
idiotism  being  common.  Indeed,  the  whole  clinical  picture  is  so  char- 
acteristic that  once  having  seen  a   case  no  one  can  fail  afterward  to 


Pig.    194.— Cretin,   nineteen  years  old.     The  treatment  with   thyroid  extract   started   too  late  to  be  ot 
benefit.      (Patient  of  Dr.   S.  J.   Webster.) 

recognize  the  disease.  Besides  being  due  to  congenital  absence  of  the 
thyroid  (sporadic  type),  cretinism  may  also  occur  as  a  result  of  goitrous 
degeneration  of  the  gland.  This  forms  the  so-called  endemic  variety  of 
the  disease,  and  is  more  commonly  seen  in  goitrous  districts,  being  not 
infrequently  associated  with  disease  of  the  parathyroid,  in  which  case 
the  nervous  symptoms  are  very  prominent. 

Atrophy  of  the  thyroid  in  adults  causes  the  clinical  condition  known 


Tin     TIIYROU)    \\l»    P  \i:  A'l'in  i:<  hi  >   <a.  wns 


,.,.. 


as  myxedema,  and  here  .-main  the  symptoms  are  very  characteristic  (Fig. 
195).  The  skin  is  dry  and  thick,  with  a  deposition  of  connective  tissue 
often  containing  Fal  in  its  deeper  layers;  the  hands  and  Feel  become 
unshapely;  the  lips  thick  and  the  tongue  somewhal  enlarged,  so  thai 
when  the  person  attempts  to  speak,  i1  appears  as  if  the  tongue  were  too 
large  For  the  mouth  ;  the  hair  Tails  ou1  ;  there  is  a  low  body  temperature, 
and  it  can  be  shown  thai  the  energy  metabolism  is  greatly  depressed,  and 
that  a  deficiency  of  oxygen  is  being  consumed,  h  is  said  the  person  can 
take  a  larger  quantity  of  sugar  than  an  ordinary  individual  without  the 
development  of  glycosuria,  1ml  the  depression  of  the  metabolic  function 

causes  the.patient  to  take  sparingly  of  t' 1.  in  spile  of  which,  however, 

ihe  body  weighl   mav  steadily  increase.     The  sexual    Function   becomes 


A.  B. 

Fig.    195. — A,    Case    of    myxedema;    B,    Same    after    sever,    months'    treatment.      (From    Tigerstedt.) 


depressed,  and  there  is  involvement  of  the  nervous  system  as  shown  by 
mental  dullness  and  lethargy. 

Although  the  thyroid  gland  is  much  atrophied  in  myxedema,  symptoms 
that  are  very  similar  may  also  occur  when  the  gland  is  enormously  en- 
larged. As  already  explained,  however,  this  enlargement  is  due  merely 
to  an  accumulation  of  colloidal  material  and  is  really  an  atrophic  con- 
dition. A  patient  suffering  from  endemic  goiter  may  at  first  exhibit 
symptoms  which  are  usually  attributed  to  a  hypersecretion  of  thyroid 
material  into  the  blood  (the  symptoms  will  he  described  immediately), 
but  later  these  give  place  to  symptoms  not  unlike  those  of  myxedema. 

It  is  concluded  that  the  above  conditions  are  due  to  deficiency  of 
thyroid  function,  or  hypothyroidism,  because:  (1)  the  gland  is  atrophied, 


7f>()  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

and  (2)  similar  symptoms  to  those  exhibited  by  the  clinical  conditions 
can  be  produced  experimentally  by  the  removal  of  the  gland  in  animals. 
By  observations  on  the  effect  of  administration  of  thyroid  extract  to 
cretinous  or  myxedematous  patients,  prompt  amelioration  of  the  symp- 
toms occurs,  which  certainly  suggests  that  the  real  cause  is  the  absence 
of  an  internal  secretion.  There  is  probably  nothing  more  striking  in 
the  whole  domain  of  therapeutics  than  this  effect  from  the  administration 
of  thyroid  extract  or,  more  so  still,  of  alpha-iodine.  If  the  treatment  is 
started  early  enough,  the  cretinous  child  from  being  an  ill-developed 
idiot  quickly  catches  up  with  children  of  his  own  age  and  becomes  in 
every  respect  normal.  Even  if  this  treatment  is  not  undertaken  until 
the  child  is  several  years  of  age,  it  is  remarkable  how  quickly  the  benefit 
may  show  itself.  In  myxedema  and  cachexia  strumipriva  also,  the 
symptoms  very  quickly  disappear  and  the  person  becomes  perfectly  nor- 
mal by  the  treatment.  In  all  these  conditions,  however,  the  thyroid 
extract  must  be  administered  continuously  in  order  to  prevent  the  reap- 
pearance of  symptoms. 

Quite  distinct  from  the  above  described  conditions  of  hypothyroidism 
are  those  produced  by  an  excess  of  thyroid  autacoid  in  the  blood,  namely, 
hyperthyroidism.  Such  a  condition  can  be  produced  experimentally  in 
normal  animals  by  the  administration  of  thyroid  extract  or  alpha-iodine 
(Kendall).  In  man  large  doses  are  soon  followed  by  great  quickening 
of  the  pulse  with  some  irregularity,  flushing  of  the  skin,  increased  per- 
spiration, tremor  in  the  limbs,  emaciation,  and  marked  nervous  excita- 
bility. Along  with  these  symptoms,  metabolic  investigations  have  shown 
that  the  energy  output  per  square  meter  of  surface  is  greatly  increased, 
being  sometimes  nearly  doubled;  that  the  nitrogen  excretion  is  exces- 
sive; and  that  alimentary  glycosuria  is  very  commonly  present.  The 
body  temperature  is  not,  hoAvever,  as  a  rule  increased,  because  although 
metabolism  is  excited,  yet  heat  loss  is  correspondingly  increased.  Ex- 
ophthalmos is  said  to  develop  very  occasionally  after  such  administra- 
tion, but  this  is  doubtful.  Lastly,  there  are  usually  digestive  disturb- 
ances, although  the  appetite  is  likely  to  be  increased.  The  pulse  is  quick- 
ened after  administration  of  alpha-iodine  only  when  protein  food  is  also 
taken.  This  is  believed  by  Kendall  to  be  due  to  the  association  between 
the  thyroid  hormone  and  the  metabolism  of  the  amino  acids. 

The  symptoms  following  the  injection  of  the  extract  are  very  similar 
to  those  of  the  disease  known  as  exoplithahnic  goiter.  Indeed,  the  symp- 
toms are  so  much  alike  in  the  two  conditions  that  it  is  scarcely  neces- 
sary to  describe  them  specially  for  the  disease  except  to  mention  that 
the  exophthalmos  is  much  more  likely  to  be  present. 

Like  simple  goiter  this  variety  is  from  three  to  four  times  more  fre- 


THE   THYROID    AND   PARATHYROID   GLANDS  757 

(|iiciit  in  women  than  in  men,  a  fact  of  significance  when  we  recall  the 
evidence  of  association  between  the  thyroid  gland  and  the  generative 
organs.  It  is  said  that  the  disease  is  usually  coupled  with  persistence  of 
the  thymus  gland.  The  thyroid  gland  in  exophthalmic  goiter  is  enlarged, 
sometimes  in  one  lobe;  it  is  hard  and  pulpy,  and  on  auscultation  a  mur- 
mur is  heard.  Histologically  the  gland  presents  a  picture  very  like 
thai  which  has  been  described  above  as  hyperplasia;  that  is  to  say,  the 
vesicles  have  a  deficiency  of  colloid  material;  their  epithelium  is  colum- 
nar and  folded  up  into  the  vesicles;  and  the  interstitial  tissue  between 
the  vesicles  is  very  markedly  increased. 

Exophthalmic  goiter  is  almost  universally  claimed  to  be  due  to  hyper- 
secretion of  the  thyroid,  because:  (1)  the  symptoms  of  the  disease  are  not 
unlike  those  produced  by  excessive  administration  of  thyroid  to  a  normal 
individual;  and  (2)  they  are  in  general  opposite  in  character  to  the  symp- 
toms found  in  cases  where  the  thyroid  gland  is  atrophied.  The  blood  of 
a  person  with  exophthalmic  goiter  when  injected  into  mice  increases  their 
resistance  to  the  toxic  action  of  acetonitrile,  which  is  also  the  case  after 
thyroid  extract  has  been  injected.  In  many  cases  of  exophthalmic  goiter 
partial  removal 'of  the  gland  is  said  to  ameliorate  the  symptoms.  Other 
clinicians,  however,  state  that  if  the  patient  is  given  proper  medical 
treatment,  rest,  and  diet,  equally  beneficial  results  can  be  obtained. 

Certain  investigators,  however,  deny  that  it  has  yet  been  conclusively 
demonstrated  that  exophthalmic  goiter  is  due  to  hypersecretion  of  the  thy- 
roid (Marine).  It  is  pointed  out  that,  if  hypersecretion  were  the  cause  of 
the  disease,  one  would  expect  that  the  injection  into  animals  of  the  blood 
of  patients  suffering  from  it  would  produce  symptoms  similar  to  those 
following  the  injection  of  thyroid  extract.  The  results  of  such  experi- 
ments, however,  have  been  extremely  confusing  and  very  indecisive,  since 
it  is  difficult  to  recognize  in  laboratory  animals  many  of  the  characteristic 
symptoms,  especially  those  affecting  the  skin  and  eyes  and  the  general 
bodily  nutrition.  Another  difficulty  in  accepting  the  hypersecretion  hypoth- 
esis is  the  fact  that  an  extract  of  a  gland  removed  from  an  exophthalmic 
patient  has  no  different  physiologic  action  on  a  normal  animal  from  an 
extract  of  a  normal  gland  containing  the  same  percentage  of  iodine. 
The  evidence  is  by  no  means  conclusive  one  way  or  the  other,  and  it  may 
well  be  that  the  observed  changes  in  the  thyroid  gland  are  not  the  cause 
of  the  symptoms  of  exophthalmic  goiter,  but  merely,  like  the  other  symp- 
toms of  this  disease,  a  result  of  some  condition  located  elsewhere. 

The  Relationship  of  the  Thyroid  with  Other  Endocrine  Organs 

1.  With  the  Generative  Organs. — Evidence  of  an  association  between 
the  female  generative  organs  and  the  thyroid  is  very  strong;  thus,  the 


758  THE    ENDOCRINE    ORGANS.    OR    DUCTLESS    GLANDS 

thyroid  becomes  enlarged  at  puberty,  during  the  menses,  and  during 
pregnancy,  and  in  thyroidectomized  young  animals  the  sexual  glands 
fail  to  develop  properly. 

2.  With  the  Adrenal  Glands.     (See  page  746.) 

3.  With  the  Pituitary  Body.  —After  removal  of  the  thyroid,  the  pitu- 
itary becomes  greatly  altered  and  enlarged,  particularly  the  pars  an- 
terior, in  which  it  is  not  uncommon  to  find  that  a  certain  amount  of 
vesicles  containing  colloid,  not  unlike  those  of  the  thyroid,  become  devel- 
oped.. This  colloid  material,  however,  does  not  contain  iodine.  It  is  said 
that  this  increase  of  the  pituitary  after  thyroidectomy  does  not  occur  if 
thyroid  extract  be  administered.  Increased  activity  of  the  pars  inter- 
media of  the  pituitary  is  also  quite  plain.  These  facts  Mould  at  first 
sight  seem  to  indicate  that  the  pituitary  and  the  thyroid  can  act  vica- 
riously, Imt  this  is  very  doubtful,  for  it  has  not  been  found  that  pitu- 
itary extract  has  any  beneficial  effect  in  the  treatment  of  goiter  and  myx- 
edema. Nevertheless  the  association  in  function  of  the  two  glands  must 
be  more  or  less  close,  not  alone  for  the  above  reasons,  but  also  because  they 
are  both  associated  to  much  the  same  degree  with  the  sexual  organs, 
and  both  act  on  the  higher  functions  of  the  nervous  system  in  much  the 
same  manner. 

4.  With  the  Thymus  Gland. — The  persistence  of  the  thymus  in  ex- 
ophthalmic goiter,  as  well  as  the  anatomic  and  embryologic  relationship 

between  thymus  and  thyroid,  is  taken  to  indicate  some  close  relationship. 

THE  PARATHYROIDS 

Experimental  Parathyroidectomy 

Experimental  parathyroidectomy  yields  results  which  vary  in  dif- 
ferent groups  of  animals,  undoubtedly  because  of  the  fact  that  in  some, 
such  as  the  rat  and  rabbit,  accessory  parathyroids  may  exist.  In  gen- 
eral, however,  it  has  been  found  that  if  more  than  two  of  the  four 
parathyroids  be  removed,  very  definite  and  pronounced  nervous  symp- 
toms soon  supervene  and  if  all  four  glands  be  removed,  a  cpiickly  fatal 
result  is  inevitable.  The  most  acute  symptoms  are  exhibited  by  the 
carnivora.  They  may  not  be  apparent  tor  a  day  or  two  after  the  opera- 
tion, although  during  the  period  the  animal  is  in  a  depressed  state,  re- 
fusing food  and  losing  weighl  rapidly.  The  muscles  are  also  more  or  less 
stiff  during  this  stage.  When  more  definite  symptoms  appear,  they  con- 
sist of  a  marked  abnormality  of  muscular  contraction,  leading  to  the 
occurrence  of  fibrillar  contractions,  or  tremors  and,  later,  to  cramp-like 
and   clonic    contractions.      When    spontaneous    movements    are    made,    a 


THK   THYROID    AND    PARATHYROID   GLANDS  759 

peculiar  shaking  of  the  foot,  Like  thai  made  by  a  normal  animal  to  Bhake 
water  off  its  pads,  is  a  characteristic  symptom.  The  slightest  stimulation 
of  the  peripheral  nen  es  is  sufficienl  to  induce  one  of  these  attacks,  which 
recur  with  ever  increasing  frequency,  becoming  at  the  same  time  more 
pronounced  and  accompanied  by  other  disturbances,  such  as  diarrhea, 
profuse  salivation,  rapid  pulse,  and  dyspnea  (in  the  dog  but  not  in  the 
cat).  In  cases  that  are  not  quickly  fatal,  the  hair  tends  to  be  shed,  and 
the  teeth  to  be  improperly  calcified  (in  young  animals).  Where  a  certain 
amount  of  parathyroid  tissue  has  been  left — for  example,  one  of  the  four 
lobes— the  symptoms  may  not  appear  except  under  conditions  of  special 
strain  to  the  animal  economy,  such  as  pregnancy  or  improper  diet. 
Thus,  in  a  bitch  from  which  three  of  the  four  glands  had  been  removed, 
no  symptoms  of  tetany  occurred  until  she  became  pregnant.  Under  the 
same  conditions  it  has  been  found  that  a  diet  of  flesh  is  much  more  apt 
to  bring  about  the  condition  than  one  of  vegetables  or  milk. 

Tetany,  as  the  above  condition  is  called,  may  also  become  developed 
in  man  either  as  the  result  of  surgical  removal  of  the  parathyroids  or 
because  of  their  improper  development.  The  symptoms  in  man  are  very 
similar  to  those  observed  in  laboratory  animals,  the  only  difference  being 
that  the  muscular  contractions  are  more  likely  to  be  tonic  in  character. 
Certain  symptoms  that  may  develop  during  pregnancy  or  in  the  course 
of  infectious  diseases  or  in  newborn  infants  have  also  been  found  to  be 
associated  with  degeneration  of  or  hemorrhage  into  the  parathyroid 
(idiopathic  tetany),  and  certain  obscure  nervous  diseases  in  adults, 
such  as  paralysis  agitans,  may  possibly  also  be  associated  with  changes 
in  this  gland.  Chorea,  epilepsy,  and  eclampsia  have  likewise  been 
thought  to  be  associated  with  it. 

The  parathyroid  gland,  besides  influencing  the  nerve  centers,  has  also 
an  influence  on  metabolism.  The  symptoms  produced  are:  (1)  rapid 
emaciation  and  failure  to  grow;  (2)  a  tendency  to  the  production  of 
glycosuria,  often  detected  by  finding  that  the  assimilation  limit  for 
carbohydrate  is  lowered  (page  652)  ;  and  (3)  most  definitely  of  all,  an 
interference  Avith  calcium  metabolism,  as  illustrated  by  the  failure  of 
the  teeth  and  bones  to  calcify  properly.  This  interference  with  normal 
metabolism  led  Kellogg  and  Voegtlin81  to  study  the  effect  produced  on 
parathyroidectomized  animals  by  the  administration  of  calcium.  It  was 
found  that  the  symptoms  were  considerably  ameliorated.  These  authors 
concluded  from  their  results  that  the  essential  cause  of  tetany  is  a 
deficiency  of  calcium  in  the  blood.  It  is  possible  however  that  the  bene- 
ficial action  of  calcium  salts  in  this  condition  is  that  it  decreases  the 
excitability  of  the  nervous  system,  an  action  which  it  is  known  to 
possess. 


760  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

When  the  tetany  is  the  result  of  a  complete  extirpation  of  all  parathy- 
roid tissue,  the  symptoms  can  be  combated  by  a  successful  transplan- 
tation or  graft  of  parathyroid  tissue  made  from  an  animal  of  the  same 
species.  Indeed,  it  has  been  found  that  the  success  of  a  graft  of  parathy- 
roid is  assured  only  when  the  graft  is  derived  from  the  same  kind  of 
animal  as  that  from  -which  the  parathyroid  has  been  removed.  Implan- 
tation into  the  subcutaneous  tissue  of  a  tetany  patient  of  parathyroid 
tissue  obtained  fresh  from  the  deadhouse  has  been  performed  with  bene- 
ficial outcome. 

Noel  Paton,  Findlay  and  Watsonso  have  recently  contributed  greatly 
to  our  knowledge  of  the  physiologic  pathology  of  tetania  thyreopriva. 
as  the  above  condition  is  called.  The  symptoms  are  not  due  to  any  con- 
dition affecting  the  muscles  themselves,  since  they  disappear  after  sec- 
tion of  the  nerves.  Nor  are  they  primarily  dependent  upon  the  cere- 
brum or  cerebellum,  since  ablation  of  neither  abolishes  them.  This  does 
not  imply  that  secondary  involvement  of  the  higher  centers  never  oc- 
•curs;  on  the  contrary,  the  epileptiform  convulsions  and  disturbances  of 
equilibrium  sometimes  observed  indicate  cerebral  or  cerebellar  involve- 
ment, respectively.  This  leaves  some  part  of  the  lower  neuron  reflex 
arcs  as  the  site  of  involvement.  It  is  not  the  afferent  neuron,  since  the 
tremors  and  jerkings  persist  after  section  of  the  posterior  roots,  leaving 
the  afferent  neuron  as  the  affected  structure. 

The  foregoing  conclusion  led  Paton  and  his  co-workers  to  compare  the 
response  of  muscle  and  nerve  to  electric  stimulation  in  normal  and 
parathyroideetomized  animals.  Although  there  are  considerable  varia- 
tions in  the  responses  of  a  normal  animal,  they  are  very  definitely  ex- 
aggerated in  tetany  when  either  the  motor  neuron  or  the  muscle  itself 
is  stimulated,  the  exaggeration  in  the  latter  case  being  dependent  upon 
alterations  in  the  neural  structures  (nerve  endings)  in  the  muscle.  The 
increased  electric  excitability  can  not,  however,  be  taken  as  a  measure 
of  the  severity  of  the  condition,  for  it  may  be  no  more  marked  in  cases 
in  which. there  is  involvement  of  the  cerebral  hemisphere  (causing  epilep- 
tiform fits)  than  in  milder  cases. 

As  to  the  cause  of  the  symptoms,  many  possibilities  have  to  be  con- 
sidered. In  the  first  place,  no  direct  relationship  exists  between  the 
thyroid  and  parathyroid  in  this  connection.  One  cause  might  be  the 
absence  of  some  substance  which  checks  the  activity  of  the  nervous  sys- 
tem, some  chalone  in  Schafer's  sense.  That  such  is  not  the  case  is  shown 
among  other  things  by  the  fact  that  bleeding  and  transfusing  normal 
saline  immediately  removes  the  symptoms  for  some  time.  Moreover, 
the  metabolic  disturbances  go  on  when  the  nervous  symptoms  are  slight. 
It  had  previously  been  thought  by   \Y.  (i.  Macalhim81  that,  since  symp- 


'I'll! 


THYROID    \M>    PARATHYROID   GLANDS  761 


toms  like  those  of  tetany  can  be  induced  by  deficiency  of  calcium  in  the 
body  and  the  symptoms  of  parathyroidectomy  relieved  by  administration 
of  this  cation,  calcium  deficiency  is  the  cause  of  the  symptoms.  While 
not  denying  thai  these  ions  may  have  some  relationship  to  the  symptoms, 
Noel  Paton  ascribes  them  to  intoxication  by  guanidine  (page  605).  The 
evidence  is  as  follows:  (1)  Guanidine  and  methyl  guanidine  admin- 
istered to  normal  animals  produce  symptoms  thai  are  identical  with  those 
following  parathyroidectomy.  (2)  There  is  a  marked  increase  in  the* 
amount  of  Ihese  substances  in  the  blood  and  urine  of  parathyroidec- 
tomized  dogs  and  in  the  urine  of  children  suffering  from  idiopathic 
tetany.  (3)  In  certain  eases  the  serum  of  parathyroidectomized  doi>'s 
acts  upon  the  muscles  of  the  frog  similarly  to  weak  solutions  of  guani- 
dine and  methyl  guanidine.  (4)  There  is  a  striking  similarity  in  the 
relative  amounts  of  the  nitrogenous  metabolites  in  the  urine  of  parathy- 
roidectomized dogs  and  of  normal  animals  injected  with  guanidine. 

It  is  concluded  that  the  parathyroids  control  the  metabolism  of  guani- 
dine "by  preventing  its  development  in  undue  amounts.  In  this  way 
they  probably  exercise  a  regulative  action  upon  the  tone  of  the  skeletal 
muscles."  Since  it  is  similar  with  regard  to  its  characters  and  metabo- 
lism to  the  condition  following  thyroidectomy,  it  is  believed  that  disease 
of  the  parathyroids  is  the  cause  of  idiopathic  tetany. 

The  Relationship  of  the  Parathyroid  with  Other  Endocrine 

Organs 

We  know  very  little  of  the  relationship  of  the  parathyroid  with  other 
endocrine  organs.  Vincent  and  others  have  stated  that  after  removal 
of  the  thyroid  itself  enlargement  of  the  parathyroid  may  occur  with  the 
formation  of  colloid  material  between  the.  rows  of  cells,  but  the  con- 
clusion that  this  represents  a  vicarious  function  between  the  thyroid  and 
parathyroid  glands  is  not  generally  accepted.  The  supposed  relation- 
ships among  the  parathyroid  and  the  pituitary  and  adrenal  glands  are 
also  based  upon  uncertain  evidence. 


CHAPTER  LXXXIV 
THE  PITUITARY  BODY 

Structural  Relationships 

Situated  at  the  base  of  the  brain  and  lying  in  the  sella  turcica,  the 
pituitary  body  in  man  does  not  weigh  much  more  than  half  a  gram.  It 
is  connected  -with  the  brain  by  a  funnel-shaped  stalk,  the  infundibulum. 
On  account  of  a  natural  cleft,  -which  runs  across  the  gland  in  an  oblique 
plane,  it  is  an  easy  matter  to  split  it  into  t-wo  portions,  an  anterior,  or 
pars  glandularis,  and  a  posterior,  or  pars  nervosa.  This  cleft  in  the 
case  of  man  is  usually  found  to  be  more  or  less  broken  up  into  isolated 
cysts  containing  a  colloid-like  material,  and  it  represents  the  remains  of 
the  original  tubular  structure  from  which  the  pars  glandularis  is  de- 
veloped ;  namely,  a  pouch  growing  out  from  the  buccal  ectoderm. 

On  histologic  examination  it  will  be  found  that  the  pars  glandularis 
consists  of  masses  of  epithelial  cells  with  large  sinus-like  blood  capil- 
laries lying  between  them.  These  blood  vessels  are  very  numerous,  so 
that  in  an  injected  gland  this  portion  of  the  pituitary  stands  out  very 
prominently.  The  vessels  are  derived  from  about  twenty  small  arterioles 
that  converge  toward  the  pituitary  from  the  circle  of  Willis,  and  enter 
the  gland  by  the  infundibulum  or  stalk  by  which  the  gland  is  connected 
with  the  base  of  the  brain.  Three  types  of  cell  can  be  differentiated: 
nonstaining  (chromaphobe)  and  granular  (chromaphil),  of  which  latter 
there  are  cells  with  acid-staining  and  others  with  base-staining  granules, 
the  former  being  by  far  the  more  numerous  (Schafer).00  In  some 
animals  such  as  the  cat,  the  cells  of  the  pars  anterior  are  arranged  around 
the  blood  sinuses  in  rows  as  in  a  columnar  epithelium.  The  cells  with 
acid-staining  granules  are  said  to  become  much  increased  in  number  in 
pregnancy  and  also  in  the  enlarged  gland  of  acromegaly  (see  page  772). 
After  thyroidectomy  it  has  been  observed  that  colloid-like  masses  ac- 
cumulate in  the  pars  glandularis,  the  cells  sometimes  arranging  them- 
selves around  these  masses  as  in  the  thyroid  gland.  The  colloid,  how- 
ever, contains  no  iodine. 

The  posterior  part  of  the  gland,  or  pars  nervosa,  is  composed  almost 
entirely  of  neuroglia,  cells,  and  fibers,  usually  with  some  hyaline  or 
granular  material  lying  between  them,  particularly  in  the  neighborhood 

762 


THE    ITl'l    ITAKY    I'.ol'Y 


763 


of  the  infundibulum,  into  which  it  may  be  traced.  It  is  believed  thai 
the  active  principle  of  the  gland  is  represented  by  this  material.  The 
l)loud  supply  of  the  pars  nervosa  is  relatively  scanty. 

Between  the  pars  nervosa  and  the  intraglandular  cleft  above  referred 
in  is  a  layer  of  cells  differing  from  those  of  either  the  anterior  or  the 
posterior  lobe.  This  layer  of  cells  constitutes  the  so-called  pars  inter- 
media. The  cells  ;ire  somewhat  like  those  of  the  pars  glandularis,  except 
that  they  are  distinctly  granular,  the  granules  being  of  the  neutrophile 
variety,  thai  is  to  say,  they  stain  \\  itli  neither  basic  nor  acid  dyes.  Well- 
defined  vesicles  containing  an  oxyphile  colloid  material  are  often  found 


Fig.  196. — Drawing  from  a  photograph  of  a  mesial  sagittal  section  through  the  pituitary  gland 
of  a  human  fetus  (5th  month):  a,  optic  chiasma;  c,  third  ventricle;  d,  pars  glandularis;  e,  infun- 
dibulum  surrounded  by  epithelial  cells;  f,  pars  intermedia;  g,  intraglandular  cleft;  h,  pars  nervosa. 
(Herring,    from    Howell's   Physiology.) 

between  them.  The  blood  supply  is  much  less  abundant  than  that  of  the 
pars  glandularis.  Although  well  separated  by  the  cleft  from  the  pars 
glandularis,  the  pars  intermedia  is  not  well  separated  from  the  pars 
nervosa,  because  many  of  its  cells  extend  for  some  distance  into  the  lat- 
ter between  the  neuroglial  fibers.  Certain  of  the  cells  in  the  pars  inter- 
media may  be  seen  in  various  stages  of  conversion  into  globular  hyaline 
bodies,  or  a  granular  mass  of  material  may  appear  in  them.  In  cither 
case,  the  cells  ultimately  break  down,  setting  free  the  hyaline  or  granular 
material,  which  is  believed  to  be  the  origin  of  the  similar  material  al- 
ready described  as  existing  between  the  neuroglial  fibers  of  the  pars 
nervosa  and  therefore  ultimately  finding  its  way  by  the  infundibulum 


764  THE    ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

into  the  third  ventricle  of  the  brain.  These  hyaline  globules  arc  greatly 
increased  after  thyroidectomy.  It  should  be  mentioned,  finally,  that  at 
the  margin  of  the  intraglandular  cleft  the  intermediary  and  anterior 
portions  of  the  pituitary  come  together,  although  the  cells  of  each  can 
readily  be  distinguished  on  account  of  their  staining  properties.  This 
pars  glandularis  et  intermedia  also  extends  as  a  thin  layer  over  part  of 
the  pai's  nervosa  and  around  the  neck  of  the  gland  at  the  infundibulum. 
These  relationships  are  well  shown  in  the  accompanying  diagram  (Fig. 
196). 

Functions 

Concerning  the  function  of  the  pituitary,  it  may  be  said  in  general  that 
the  anterior  lobe  has  an  important  relationship  to  the  nutritive  con- 
dition of  the  body  during  growth,  especially  of  the  skeletal  structures, 
and  that  the  posterior  lobe  produces  a  very  active  autacoid  having  to  do 
with  the  physiologic  activity  of  unstriped  muscle  fiber.  The  pars  inter- 
media seems  to  be  associated  with  the  posterior  lobe  in  the  production  of 
this  autacoid.  The  function  of  these  two  parts  will  therefore  be  con- 
sidered together. 

Function  of  the  Pars  Glandularis. — The  facts  concerning  the  function 
of  the  pars  glandularis  have  been  gleaned  largely  by  observing  the  ef- 
fects produced  by  partial  or  complete  removal  of  the  entire  pituitary, 
justification  for  ascribing  to  the  removal  of  the  anterior,  rather  than 
the  posterior,  lobe  the  results  that  are  obtained  being  furnished  by  control 
experiments,  in  which  by  removal  of  the  posterior  lobe  alone  similar 
effects  are  not  observed. 

Complete  removal  of  the  pituitary  is  almost  invariably  fatal,  the  con- 
dition being  called  apituitarism.  Two  operative  procedures  have  been 
employed  for  the  removal  of  the  gland.  One  of  these,  elaborated  by  Cushing 
and  his  pupils,52  consists  in  trephining  the  skull  and  elevating  the  temporal 
lobe  of  the  cerebrum  so  as  to  expose  the  gland.  The  other,  elaborated 
by  Horsley,83  consists  in  approaching  the  gland  through  the  orbital 
cavity.  Although  there  is  some  danger  of  injury  to  nervous  tissues  by 
the  intracranial  method,  its  results  are  more  dependable  since  the  gland 
is  actually  exposed  to  view  before  being  removed. 

Most  hypophysectomized  animals  die  within  two  or  three  days,  unless 
they  are  very  young.  This  longer  survival  of  young  animals  is  ascribed 
to  the  presence  of  accessory  pituitary  material  situated  in  the  dura  mater 
lining  the  sella  turcica.  The  most  extensive  observations  have  been  made 
on  dogs.  On  the  day  following  the  operation  the  animal  appears  about 
normal,  but  it  gradually  becomes  less  active,  refusing  food  and  respond- 
ing slowly  to  stimulation.    It  gradually  gets  weaker  and  weaker;  muscu- 


THE    I  II  I   IT  \i;\     BODY  7li-"» 

lar  tremors  may  appear,  the  respiration  and  pulse  become  Blow,  the  back 
arched,  the  temperature  subnormal;  and,  usually  within  aboul  Corty- 
eighl  hours,  coma  develops  and  the  animal  dies  in  this  condition.  When 
the  symptoms  are  less  acute  and  death  does  nol  occur  so  early,  if  is 
believed  by  Cushing  either  thai  small  portions  of  the  gland  have  been 
left  behind  or  that  some  vicarious  activity  of  other  organs  lias  developed 
to  replace  that  of  the  pituitary. 

When  only  a  pari  of  the  pituitary  is  removed  either  unintentionally 
or  intentionally,  the  symptoms  are  no1  nearly  so  acute,  and  the  condition 
is  known  as  hypopiUdtarism.  It  is  by  a  study  of  this  condition  thai 
most  facts  concerning  the  fund  ion  of  the  anterior  lobe  have  been  learned. 
When  the  operation  is  performed  on  young  animals,  they  fail  to  grow 
properly;  the  milk  teeth  and  the  lanugo  are  retained;  the  epiphyses 
do  not  ankylose;  the  thyroid  and  thymus  glands  ave  enlarged;  and  the 
cortex  of  the  suprarenal  and  the  sexual  organs  fails  to  develop.  The 
animal,  though  small,  beeomes  very  fat  and  may  therefore  increase  in 
weight.  There  is  distinct  evidence  of  mental  dullness.  From  these 
results  it  is  concluded  that  the  anterior  lobe  of  the  pituitary  produees 
autaeoiels  having  to  do  with  tin  development  of  the  slxfhlul  and  other 
structures  of  the  growing  animal.  That  this  autacoid  is  not  derived  from 
the  posterior  lobe  is  evidenced  by  the  fact  that  partial  injury  of  this 
lobe,  or  indeed  its  entire  removal,  is  not  followed  by  similar  symptoms. 

Closer  examination  of  the  metabolic  function  in  hypophysectomized 
animals  has  shown  that  there  is  a  marked  depression  in  the  respiratory 
exchange  of  oxygen  and  carbon  dioxide,  and  that  the  ability  to  metabo- 
lize carbohydrate  becomes  heightened;  that  is  to  say,  the  animal  with- 
out developing  glycosuria  can  tolerate  a  larger  quantity  of  sugar  than 
the  normal  animal.  This  effect  on  carbohydrate  metabolism  may  how- 
ever be  associated  not  so  much  with  the  function  of  the  anterior  lobe  as 
with  that  of  the  posterior,  for,  as  we  shall  see  later,  Cushing  and  his 
pupils  have  found  that  extract  of  the  posterior  lobe  has  a  marked  effect 
on  the  assimilation  limit  of  carbohydrate. 

Attempts  have  been  made  to  graft  the  pituitary,  especially  the  anterior 
lobe,  into  various  parts  of  the  body.  It  has  been  found,  however,  that 
within  a  few  days  the  grafts  atrophy  and  disappear  unless  there  has 
been  complete  removal  of  the  pituitary  itself,  in  which  case  the  graft 
may  remain  for  a  month  or  so  and  the  otherwise  fatal  outcome  of  hypophy- 
sectomy  be  warded  off.  Sometimes,  where  the  graft  has  remained  for  a 
longer  time,  it  is  said  that  a  temporary  increase  in  the  growth  of  the 
animal  has  been  noticed. 

Other  observers  have  investigated  the  effects  in  normal  animals  of 
continuous  oral  administration  of  pituitary  substance  or  of  subcutaneous 


766  'Mil     ENDOCRINE    ORGANS,    OK    DUCTLESS    GLANDS 

injection  of  extract.  The  earlier  results  were  indefinite  and  confusing, 
but  recently  Brailsford  Robertson*1  has  succeeded  in  isolating  from  the 
anterior  lobe  a  substance  called  tethelin,  which  accelerates  growth  in 
young  animals  and  is  thought  to  have  a  possihle  value  in  hastening  the 
healing  process  in  wounds. 

Tethelin  is  precipitated  by  dry  ether  from  an  alcoholic  extract  of  the 
carefully  isolated  anterior  lobes.  It  contains  1.4  per  cent  of  phosphorus 
and  nitrogen  in  the  proportion  of  four  atoms  for  every  atom  of  phos- 
phorus, two  of  the  nitrogen  atoms  being  presenl  as  amino  groups  and 
one  in  an  imino  group.  The  effects  on  growth  of  mice  are  in  every  par- 
ticular like  those  of  the  administration  of  anterior  lobes,  and  consist  in 
retardation  of  the  first  portion  of  the  third  growth  cycle,*  followed  by 
acceleration  of  the  latter  portion  of  this  cycle.  When  fully  grown, 
tethelin-fed  mice  also  differ  from  normal  animals  in  being  smaller-  in 
size  but  of  greater  weight,  with  a  distinct  difference  in  the  condition  of 
the  coat.  Normal  animals  at  fourteen  months  of  age  have  "sha'__ 
staring  and  discolored  coats,"  Avhereas  in  tethelin-fed  animals  they  have 
the  glossy  and  silky  appearance  of  young  animals.  During  growth,  nor- 
mal animals  display  a  greater  variability  in  weight  than  tethelin-fed 
animals. 

Extraordinary  effects  have  been  observed  by  Clark'"  to  be  produced 
by  feeding  laying  hens  with  pituitary  gland.  Thus,  by  giving  to  one- 
year-old  hens,  in  addition  to  their  usual  food,  20  milligrams  of  fresh 
pituitary  substance  for  four  days,  it  was  found  that  the  average  daily 
number  of  eggs  laid  by  a  batch  of  655  hens  was  raised  from  273  during 
the  four  days  preceding  the  pituitary  feeding  to  352  during  the  four 
days  of  the  administration,  these  results  being  obtained  at  a  time  of 
year  when  the  natural  egg-production  of  the  hens  was  diminishing.  It 
was  further  observed  that  not  only  is  the  output  of  eggs  greatly  increased 
as  a  result  of  the  pituitary  feeding,  but  likewise  their  fertility,  for  in 
another  experiment  in  which  35  hens  were  kept  along  with  two  cockerels 
of  the  same  breed,  not  only  was  the  output  of  eggs  increased  (from  18  up 
to  33),  but  the  fertility  of  tin-  eggs  was  greatly  enhanced. 

Functions  of  the  Posterior  Lobe  or  Pars  Nervosa. — As  already  men- 
tioned, excision  of  this  part  of  the  pituitary  can  be  tolerably  well  with- 
stood by  the  animal,  so  much  so  indeed  that  from  its  behavior  after  the 
operation  we  can  conclude  little  as  to  the  function  of  the  lobe.  On  the 
other  hand,  extracts  of  the  posterior  lobe  injected  into  normal  animals 
produce  effects  that  are  very  striking,  indicating  that  the  main  function 


*Robertson  has  contributed  valuable  and  very  extensive  data  on  the  normal  curve  of  growth  of 
white  mice  kept  under  carefully  controlled  conditions.  Three  growth  cycles  are  present:  the  first 
attains  its  maximum  velocity  between  seven  and  fourteen  days  after  birth;  the  second,  between 
twenty-one  and  twenty-eight  days;  and!  the  third  about  six  weeks,  after  which  the  velocity  decreases 
progressively,   until   further   growth   ceases  between   the    fiftieth    and    sixtieth   weeks   succeeding   birth. 


THE    PITUITARY    ROD"?  7P>7 

of  this  lobe  is  production  of  an  au1 >id.    The  extracts  have  more  or  less  an 

epinephrine-like  action.  Such  extracts,  rendered  protein-free  and  steril- 
ized, are  obtainable  on  the  market  under  the  various  names  of  pituitrin, 
hypophysin,  etc.  From  them  a  crystallizable  material  has  been  obtained, 
but  tins  is  probably  a  mixture  of  various  substances.  In  discussing  the 
functions  of  these  various  extracts,  it  must  be  remembered  thai  the  inter 
mediary  pari  (pars  intermedia)  is  included  with  tlie  posterior  lobe  in 
their  preparation. 

Although  the  effect  of  pituitary  extract  on  plain  muscle  fiber  (and  on 
glandular  tissue)  appears,  on  first  sight,  to  be  very  like  that  produced 
by  epinephrine,  it  has  been  found  on  closer  examination  that  the  two 
substances  really  act  in  different  ways.  The  rise  in  blood  pressure  pro- 
duced by  pituitary  autacoid  is  likely  to  be  more  prolonged  than  that 
produced  by  epinephrine.  It  stimulates  increased  cardiac  activity,  but 
after  the  vagi  have  been  cut  or  sufficient  atropine  administered  to  para- 
lyze them,  the  pituitary  autacoid  continues  to  stimulate  the  strength  of 
the  heartbeat  without  producing  the  acceleration  noted  with  epinephrine. 
Whereas  epinephrine  has  little  or  no  action  on  the  coronary  vessels  or 
on  those  of  the  lungs,  pituitary  autacoid  usually  produces  constriction  of 
both  types  of  vessel;  and  on  the  renal  arteries  the  actions  of  the  two 
autacoids  are  entirely  different,  for  epinephrine  has  a  marked  constric- 
ing  effect,  while  the  pituitary  autacoid  produces  dilatation. 

Another  striking  difference  in  the  extracts  from  the  two  glands  is  re- 
vealed by  repeating  the  injection  after  the  effect  of  a  previous  one  has 
completely  passed  off.  With  epinephrine  the  original  effect  is  repro- 
duced ;  with  pituitrin,  on  the  other  hand,  the  effect  of  the  second  injec- 
tion is  very  often  the  reverse  of  that  of  the  first;  that  is  to  say,  the  blood 
pressure,  instead  of  rising,  may  fall,  or  the  rise  be  very  much  less 
marked.  Whether  this  effect  of  the  second  dose  is  caused  by  the  action 
of  an  autacoid  having  a  chalonic  rather  than  a  hormonic  influence,  or 
whether  it  is  due  to  a  reversed  effect  of  the  same  hormone,  it  is  impos- 
sible at  present  to  say.  The  chalonic  effect  in  any  case  is  much  more 
evanescent  than  the  hormonic,  and  it  is  not  caused  by  cholin,  as  some 
have  suggested.  The  effect  of  epinephrine,  it  will  be  remembered,  is 
abolished  by  ergotoxin  and  apocodeine.  These  drugs,  on  the  other  hand, 
have  no  influence  on  the  action  of  pituitrin.  The  difference  in  action 
between  the  two  autacoids  is  usually  explained  by  assuming  that  the 
epinephrine  acts  on  the  receptor  substance  associated  in  some  way  with 
terminations  of  the  sympathetic  nerve  fibers  in  involuntary  muscle, 
whereas  pituitrin  acts  directly  on  the  involuntary  muscle  fibers  themselves. 

Other  types  of  involuntary  fiber  are  also  acted  on  by  pituitrin.  The 
uterine  contractions  for  example  are  stimulated  (Fig.  197)  ;  so  are  those  of 


768 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 


the  intestine  (in  contrast  to  the  inhibiting  effect  of  epinephrine),  and  of  the 
bladder-ureter  musculature.     Dilatation  of  the  pupil  of  the  excised  frog 


fp:&<lftL»A&UL*JS«\ 


Fi„    197— Tracing  showing  the  action   of   pituitrin  on   the   uterine  contractions  and   blood  pressure 
in  a  dog.     Made  by  Barbour's  method.      (From  Jackson.) 

eye  is  produced.    The  effect  of  pituitrin  on  the  muscle  of  the  bronchioles 
is  shown  in  Fig.  198. 

The  glands  on  which  the  pituitrin  has  the  most  pronounced  action  are 


Till'    I'lTIITAKY     I'.OHY 


769 


the  mammary  glands  and  the  kidneys.  Tht  effect  on  the  kidney  is  evi- 
denced by  the  remarkable  increase  in  the  urinary  (low  following  injection 
of  the  pituitrin.  This  diuresis  might  of  course  be  due  merely  to  the 
vasodilatation  thai  we  have  seen  such  extracts  produce — a  vasodilatation 
which  is  all  the  more  marked  because  the  vessels  elsewhere  in  the  body 
undergo  constriction.  But  pituitrin  continues  to  cause  increased  urinary 
outflow  in  the  absence  of  any  demonstrable  vascular  change;  it  also  acts 
after  the  administration  of  atropine,  so  that  it  is  considered  by  most 
observers  to  act  on  the  excretory  epithelium  of  the  convoluted  tubules 


Fig.    198. — Tracing   showing   the    constricting   action   of   pituitrin    on    the    bronchioles   and    its    effect 
on  blood  pressure  in  a  spinal  dog.      (From  Jackson.) 

in  much  the  same  way  as  certain  diuretics,  like  diuretin.  This  renal 
hormonic  action  of  pituitrin  would  appear  to  be  analogous  with  that  of 
secretin  on  the  epithelium  of  the  pancreas.  Another  reason  for  believ- 
ing that  the.  secretory  hormone  is  independent  of  that  producing  vaso- 
dilatation of  the  renal  vessels  is  the  fact  that  a  repeated  dose  of  pituitrin, 
although,  as  we  have  seen,  it  usually  has  a  depressor  action  on  the  blood 
vessels,  'still  produces  a  stimulating  effect  on  the  excretion  of  urine. 
The  value  of  pituitrin  as  a  diuretic  in  clinical  practice  is  now  well 
recognized. 

The  effect  on  milk  secretion  is  best  demonstrated  by  placing  a  cannula 


770  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

in  the  mammary  ducts  so  that  the  milk  may  freely  flow  out.  By  observ- 
ing the  rate  of  outflow  during  the  injection  of  pituitrin,  it  will  be  found 
that  a  remarkable  increase  occurs.  After  this  increased  secretion  has 
ceased,  however,  the  injection  of  more  pituitrin  has  no  further  effect, 
indicating  that  the  influence  of  the  first  injection  must  have  been,  not  so 
much  to  stimulate  the  secretion  of  milk,  as  to  accelerate  the  outflow  of 
that  which  previously  had  been  secreted  and  had  collected  in  the  alveoli 
and  ducts.  This  effect  explains  why  the  pituitary  galactagogue  should 
have  very  little  if  any  effect  on  the  total  production  of  milk  or  on  the 
total  amount  of  fat  and  other  constituents  contained  in  it.  Histologic 
examination  of  sections  of  a  resting  mammary  gland  and  of  the  same 
gland  after  administration  of  the  pituitrin,  bears  out  the  above  interpre- 
tation of  the  action.  Alveoli  in  the  resting  state  will  be  found  largely 
distended  with  milk  and  the  epithelium  flattened  against  the  basal  mem- 
brane, whereas  alveoli  from  the  gland  after  pituitary  activity  show  small 
shriveled-up  alveoli,  containing  little  milk,  and  with  epithelium  that  is 
well  marked  and  stands  out  prominently  from  the  basal  membrane. 

These  facts  taken  together  indicate  that  pituitrin  stimulates  the  mus- 
cular fibers  of  the  ducts  of  the  mammary  glands,  thus  squeezing  out  the 
milk  contained  in  them.  Muscular  fibers  have  been  described  as  existing 
between  the  basal  membrane  and  epithelial  cells,  much  in  the  same  way 
as  they  do  in  the  case  of  the  sweat  glands.  At  least  Schafer  has  suc- 
ceeded in  demonstrating  in  this  position  rod-shaped  nuclei  which  prob- 
ably belong  to  muscular  fibers.00  By  their  contraction,  the  milk  in  the 
alveoli  is  expelled  into  the  ducts.  It  has  also  been  found  that  pituitrin 
stimulates  the  secretion  of  cerebrospinal  fluid,  and  that  this  stimulation 
is  independent  of  a  rise  in  blood  pressure. 

Pituitrin  has  a  distinct  effect  on  carbohydrate  metabolism.  After  its 
intravenous  or  subcutaneous  injection,  a  marked  lowering  in  the  toler- 
ance for  sugar  is  observed  (page  652),  usually  to  such  an  extent  that 
glycosuria  becomes  established,  dishing  and  his  pupils  have  concluded 
that  the  posterior  lobe  contributes  an  autacoid  which  stimulates  the  utili- 
zation of  sugar  in  the  body.  Confirmatory  evidence  for  this  view  is  fur- 
nished by  the  observation  that  mechanical  stimulation  of  the  posterior 
lobe,  such  as  is  produced  by  puncturing  it  with  a  needle,  is  followed  by 
a  temporary  glycosuria,  which  is  said  to  be  as  pronounced  as  that  fol- 
lowing puncture  of  the  diabetic  center  (page  672),  provided  glycogen  is 
present  in  the  liver.  The  production  of  this  carbohydrate  autacoid  would 
appear  to  be  under  the  control  of  the  S3rmpathetic  nervous  system,  for  it 
has  been  found  by  Cushing  and  others  that  stimulation  of  the  superior 
cervical  ganglion,  which  has  been  known  for  many  years  to  be  fre- 
quently followed  by  glycosuria,  has  this  effect  only  provided  the  posterior 


THE    1'ITI   ITAUY    1:<H>V 


771 


lobe  of  the  pituitary  is  intact.  Even  surgical  manipulation  <>f  the  pitui- 
tary may  excite  a  hypersecretion  of  pituitrin,  which  would  account  for 
the   glycosuria   often  observed   after   experimental   excision   or   partial 

destruction  of  the  pituitary.  A  similar  irritation  may  be  set  up  in  disease 
of  the  gland. 

The  glycosuria  which  is  usually  observed  after  partial  hypophysectomy 
soon  passes  off,  to  be  followed  by  a  permanent  condition  of  increased 
tolerance  for  sugar,  because  now  less  pituitrin  is  being  produced.  It  is 
said  that  during  the  stage  of  increased  tolerance  diabetes  can  not  be  pro- 
duced even  by  excision  of  the  pancreas.  The  glycosuria  produced  by 
irritation  of  the  posterior  lobe  is  accompanied  by  a  marked  polyuria  (dia- 
betes insipidus),  which  may  outlast  the  glycosuria. 


A. 


B. 


Fig.    199. — A,    To    show    the    appearance    before    the    onset    of    acromegalic    symptoms;    B,    The    ap- 
pearance  after   seventeen   years   of   the   disease.      (After    Campbell    Geddes. ) 


Clinical  Characteristics 

Because  of  their  importance  from  a  physiologic  standpoint,  we  shall 
now  proceed  to  review  briefly  some  of  the  more  important  facts  that  have 
so  far  been  brought  to  light  by  clinical  observations.  The  pathologic 
condition  most  frequently  observed  affecting  the  pituitary  is  an  adenom- 
atous growth  particularly  located  in  the  anterior  lobe.  Besides  pro- 
ducing general  symptoms  of  pressure,  such  as  diminution  of  the  visual 
field  and,  perhaps,  headache,  a  shadow  can  usually  be  observed  when  the 
patient  is  examined  by  means  of  the  x-rays.  General  symptoms,  com- 
monly ascribed  to  a  hypersecretion  of  the  autacoid  of  the  anterior  lobe  of 
the  pituitary — hyperpituitarism — begin    sooner    or   later    to    show   them- 


772 


THK    ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 


selves.  These  symptoms  are  almost  exactly  opposite  in  character  to  those 
observed  in  animals  after  removal  of  this  portion  of  the  gland.  Thus, 
the  bones  of  the  extremities  and  of  the  face  become  stimulated  to  in- 
creased growth,  so  that  if  the  patient  is  young,  and  the  epiphyses  there- 
fore not  ossified,  remarkable  elongation  of  the  long  bones  occurs,  pro- 
ducing the  condition  known  as  gigantism.  On  the  other  hand,  if  the  dis- 
ease does  not  develop  until  after  ossification  is  complete,  its  effects  be- 
come most  marked  in  the  bones  of  the  face,  the  lower  jaw  becoming 


Fig.    200. — Hand   of   a   person   affected   with    acromegaly. 

enormously  hypertrophied  and  the  supraorbital  ridges  very  prominent. 
The  long  bones  also  become  enlarged  at  their  extremities,  and  there  may 
be  some  increase  in  length  of  the  vertebral  column,  although  the  stature 
does  not  increase  because  of  kyphosis  (curvature  of  the  spine).  The 
condition  is. called  acromegaly.  Nutritive  disturbances  of  the  skin  and 
hairs  also  become  marked,  causing  the  skin  to  become  dry  and  yellowish, 
and  the  hairs  to  undergo  abnormal  increase  over  the  body.  An  early 
symptom  of  the  condition  is  a  failure  of  the  sexual  power  (Figs.  199 
and  200.) 


THE    PITUITARY    BODY  773 

After  a  time  the  disease  begins  to  affect  the  pars  intermedia  et  nervosa, 
and  disturbances  in  carbohydrate  metabolism  come  to  be  observed,  con- 
sisting usually  in  a  diminished  tolerance  accompanied  by  glycosuria,  in 
the  early  stages  of  the  disease,  followed  by  increased  tolerance  in  the 
later  stages.    The  glycosuria  is  usually  accompanied  by  marked  polyuria. 

It  should  be  observed  that  sometimes  tumor  of  the  pituitary  has  been 
found  to  exist  postmortem  though  none  of  the  above  symptoms  had  been 
recorded  during  life.  In  these  cases  it  is  probable  that  the  disease  from 
the  start  had  been  of  such  a  nature  as  to  produce  a  tendency  to  hypo- 
pituitarism rather  than  hyperpituitarism,  for  the  symptoms  are  very  like 
those  observed  in  animals  after  partial  or  complete  removal  of  the  gland. 
If  the  condition  commences  before  adolescence,  the  body  fails  to  grow, 
although  the  child  may  continue  to  increase  in  weight  because  of  the 
remarkable  deposition  of  fat  in  the  tissues.  Sexual  development  is  strik- 
ingly interfered  with,  and  the  secondary  sexual  characteristics  fail  to 
show  themselves.  In  boys,  for  example,  the  pubic  hairs  fail  to  extend  up 
to  the  umbilicus;  and  the  hairs  on  the  chin  do  not  develop,  whereas  the 
hair  of  the  scalp  grows  profusely.  The  bones  remain  of  the  female  type, 
and  a  broad  pelvis,  rounded  limbs,  small  feet  and  hands  are  often  ob- 
served. In  these  cases  there  is  usually  excessive  tolerance  for  carbohy- 
drates, which  may  explain  the  adiposity,  sugar  being  converted  into  fat. 
In  the  light  of  the  experimental  results,  the  effect  on  carbohydrate 
metabolism  may  be  explained  as  due  to  involvement  of  the  posterior 
lobe.  Mental  development  is  retarded,  and  psychic  derangements  are 
sometimes  observed. 

Where  the  hypopituitarism  does  not  develop  until  after  adolescence, 
some  of  the  above  symptoms  will  of  course  be  missed,  but  many  will  be 
observed,  such  as  dryness  of  the  skin,  loss  of  hair,  and  the  tendency  in 
the  male  to  adopt  certain  of  the  female  characteristics,  particularly  with 
regard  to  the  growth  of  hair.  Obesity  and  increased  tolerance  for  sugar 
are  also  evident,  and  pigmentation  of  the  skin,  something  like  that  of 
Addison's  disease,  is  said  often  to  be  a  prominent  feature.  Operative 
interference  in  the  early  stages  in  many  of  these  cases  is  of  undoubted 
benefit,  as  is  shown  by  the  brilliant  work  of  Harvey  dishing,  to  which 
the  reader  is  referred  for  further  information. 

The  Relationship  of  the  Pituitary  Gland  with  Other  Endocrine 

Organs 

The  relationship  of  the  pituitary  gland  with  other  endocrine  organs 
seems  to  be  an  intimate  one. 

1.  With  the  Thyroid  and  Parathyroid  Glands. — That  enlargement  of 
the  pituitary  occurs  after  thyroidectomy  in  man  has  been  known  for  a 


774  THE   ENDOCRINE    ORGANS,    OR   DUCTLESS   GLANDS 

considerable  number  of  years.  The  enlargement  affects  more  particu- 
larly the  pars  anterior,  although  changes  are  also  described  in  the  pars 
intermedia  et  nervosa,  Accompanying  the  enlargement  of  the  anterior 
lobe,  vesicles  containing  colloid-like  material  often  become  developed  in 
it,  but  even  after  the  hypertrophy  has  proceeded  to  a  considerable  de- 
gree, this  colloid  does  not  contain  iodine,  nor  does  an  extract  have  the 
same  physiologic  effect  as  one  of  the  thyroid  gland.  It  can  not  replace 
thyroid  extract  in  the  treatment  of  patients  Avith  goiter  or  myxedema, 
or  ameliorate  the  symptoms  produced  in  animals  by  the  removal  of  the 
thyroid  gland.  Deposition  of  colloid-like  material  in  the  pars  anterior 
also  occurs  in  myxedema.  Histologic  changes  in  the  pars  intermedia  et 
nervosa,  although  less  pronounced  than  in  the  pars  anterior,  are  never- 
theless said  to  be  perfectly  distinct  following  thyroidectomy,  and  to  con- 
sist in  an  increase  in  the  hyaline  and  granular  masses  which  have  already 
been  described  as  present  to  a  certain  extent  in  the  normal  gland. 

Less  direct  evidence  of  an  association  in  function  between  the  pituitary 
and  the  thyroid  is  furnished  by  the  similarity  of  the  effects  produced  on 
the  sexual  functions  and  on  the  general  development  of  young  animals 
by  the  removal  of  either  gland.  In  both  cases  the  animals  fail  to  grow 
properly ;  the  sexual  organs  remain  undeveloped ;  and  the  mental  func- 
tions are  infantile  in  type.  In  hypophysial  deficiency,  however,  extreme 
adiposity  is  likely  to  be  more  marked  than  is  the  case  in  cretinism. 

2.  With  the  Sexual  Organs. — That  the  pituitary  gland  has  much  to  do 
with  the  development  of  the  sexual  organs  has  already  been  shown.  Fur- 
ther evidence  of  a  relationship  between  the  sexual  glands  and  the  pitui- 
tary is  furnished  by  the  following  observations.  After  castration  en- 
largement occurs  in  the  pituitary,  and  on  histologic  examination  the 
gland  is  found  to  contain  a  large  number  of  oxyphile  cells,  particularly, 
in  the  pars  anterior.  This  influence  of  the  sexual  glands  on  the  pituitary 
is  believed  to  depend  on  the  interstitial  cells  present  in  them,  for  it  has 
been  found  that  if  the  ovary  or  testis  is  transplanted  into  other  parts  of 
the  body  after  the  castration,  the  changes  in  the  pituitary  do  not  occur, 
although,  as  we  shall  see,  the  transplanted  gland  becomes  entirely 
atrophied  except  for  the  interstitial  cells.  The  enlargement  of  the  pitui- 
tary during  pregnancy — an  enlargement  which  often  brings  it  to  two  or 
three  times  its  normal  weight — is  further  evidence  of  its  association 
with  the  ovary. 

3.  With  the  Suprarenals. — Association  of  function  is  suggested  in  this 
case  by  the  fact  that  extracts  of  suprarenal  and  pituitary  have  very  much 
the  same  effects  on  involuntary  muscular  fiber  and  glandular  structures, 
and  it  is  said  that  the  two  extracts  mutually  facilitate  each  other's 
action  in  this  regard.    It  should  be  remembered,  however,  that  pituitrin 


THE    PITUITARY    BOD'S  775 

and  epinephrine  <l<»  no1  appear  to  ael   on  exactly  the  same  peripheral 
mechanism  I  see  page  767). 

4.  With  the  Isles  of  Langerhans.  Since  pituitrin  affects  carbohydrate 
metabolism,  which  is  though.1  to  be  primarily  controlled  by  the  Isles  of 
Langerhans,  if  is  claimed  by  some  observers  thai  a  relationship  also 
exisis  between  the  pituitary  and  these  structures,  [njections  of  duodenal 
extracts  are  also  said  to  cause  a  hypersecretion  of  pituitrin  into  the 
cerebrospinal  fluid. 


CHAPTER  LXXXY 
THE  PINEAL  GLAND  AND  THE  GONADS 

THE  PINEAL  GLAND 

This  peculiar  structure  lies  between  the  anterior  corpora  quadrigem- 
ina,  and  weighs  about  two-tenths  of  a  gram.  It  is  largest  in  the  early 
years  of  life,  and  undergoes  retrogressive  changes  after  puberty.  Micro- 
scopically it  consists  of  epithelial  cells  arranged  loosely  in  trabecular, 
with  large  sinus-like  capillaries  between  them;  neuroglia  and  sometimes 
muscle-fiber  cells  are  also  present.  Curious  globules  of  calcareous  mat- 
ter (brain-sand)  are  also  found,  especially  in  the  pineal  gland  of  man. 
The  gland  is  developed  from  an  evagination  of  the  third  ventricle,  and 
\t  is  homologous  with  the  so-called  median  eye  of  reptiles. 

The  functions  of  the  pineal  gland  are  obscure.  In  cases  where  its 
extirpation  has  been  successfully  accomplished  (in  the  fowl),  it  has  been 
found  that  the  body  growth  is  stimulated  and  the  sexual  characteristics 
developed  more  quickly.  This  result  would  seem  to  indicate  that  the 
clinical  observation  that  tumors  of  the  pineal  gland  are  associated  in 
young  boys  with  abnormal  growth  of  the  skeleton  and  with  the  early 
development  of  the  secondary  sexual  characteristics,  depends  on  the 
fact  that  a  condition  of  hypopinealism  is  produced  by  the  growth  of  a 
tumor.  The  immediate  effects  of  the  injection  of  extract  of  pineal  gland 
are  not  characteristic,  consisting  merely  of  a  fall  in  blood  pressure,  which 
is,  however,  obtainable  when  an  extract  of  practically  any  cellular  organ 
is  injected.  Prolonged  administration  of  an  extract  to  growing  animals 
is  said  to  accelerate  the  growth  and  to  bring  about  a  precociou?  develop- 
ment of  the  sexual  organs;  but  this  result  is  somewhat  difficult  to  inter- 
pret, for,  as  we  have  just  seen,  similar  changes  occur  after  experimental 
removal  of  the  gland. 

THE  GONADS  OR  THE  GENERATIVE  ORGANS 

The  Generative  Glands  of  the  Male 

The  structures  which  are  responsible  for  the  well-known  influence  of 
the  testicles  on  the  development  of  the  male  sexual  characteristics  are 
the  so-called  interstitial  cells  of  Leydig,  which  consist  of  polygonal- 
shaped  epithelial-like  eells,  with  well-marked  nuclei  and  nucleoli.    Lipoid 

77(i 


THE    PINEAL   GLAND    .WD   THE   GONADS  i  I  i 

granules,  staining  black  with  osmic  acid,  are  also  present  in  the  cyto- 
plasm. The  degree  of  development  of  the  interstitial  cells  varies  in  dif- 
ferent animals,  being  marked  in  the  cat  and  man  and  ill-marked  in  the 
rat  and  rabbit.  In  animals  "which  show  seasonal  changes  in  sexual  activ- 
ity, the  cells  are  most  prominent  between  the  periods  of  sexual  activity, 
when  the  semeniferous  epithelium  is  less  evident.  They  also  become 
prominent  in  cases  where  the  semeniferous  epithelium  is  atrophied, 
either  as  a  result  of  disease  or  following  ligation  of  the  vas  deferens  done 
in  such  a  way  that  the  artery  and  nerves  to  the  testicles  are  not  included 
in  the  ligature.  When  the  testicle  or  a  portion  of  it  is  grafted  into 
another  part  of  the  body,  the  semeniferous  epithelium  degenerates,  but 
the  interstitial  cells  remain  alive  and  become  quite  prominent.  It  is 
believed  that  the  interstitial  cells  are  responsible  for  the  production  of 
an  autacoid  that  has  to  do  with  the  development  of  accessory  sexual 
characteristics. 

Tlu  effects  of  castration  are  not  significant  in  animals  below  the  verte- 
brata.  In  all  of  these,  however,  they  are  very  pronounced.  The  cas- 
trated male  frog  fails  to  show  development  of  the  thumb  pad,  but  this 
development  immediately  ensues  if  portions  of  testis  from  another  frog 
be  placed  in  the  dorsal  lymph  sac.  In  birds  the  results  are  more  pro- 
nounced; in  the  castrated  male  chick  the  comb,  spurs,  wattles,  etc.,  fail  to 
develop,  but  will  usually  do  so  if  some  testis  from  another  bird  is  trans- 
planted into  its  tissues.  In  mammals  the  effects  are  most  striking  in 
animals  that  develop  marked  male  characteristics,  such  as  the  growth 
of  antlers  in  stags.  These  fail  to  develop  properly  and  are  prematurely 
shed  after  castration.  In  man  also,  as  is  well-known  from  a  study  of 
eunuchs,  castration  has  a  very  profound  effect.  Hair  fails  to  grow  on  the 
face;  the  larynx  remains  undeveloped:  the  epiphyses  are  a  long  time  in 
ossifying,  so  that  the  stature  may  become  great,  but  at  the  same  time 
the  limb  bones  may  be  more  delicate  than  usual:  the  sutures  of  the  skull 
are  slow  in  closing;  and  the  whole  architecture  of  a  castrated  male  comes 
to  be  very  like  that  of  the  female.  Confirmatory  evidence  of  the  influ- 
ence of  the  testicles  on  the  development  of  secondary  sexual  character- 
istics is  afforded  by  the  observation  that  malignant  tumors  of  the  testes 
in  boys  are  associated  with  the  premature  development  of  the  secondary 
sexual  characteristics,  and  that  these  may  recede  after  the  removal  of 
the  tumor. 

As  a  result  of  castration,  interesting  changes  have  also  been  observed 
in  other  ductless  glands.  Thus,  the  suprarenal  cortex  and  the  thymus 
become  enlarged,  whereas  the  thyroid  and  pituitary  become  atrophied. 
The  metabolic  functions  also  become  tardy,  as  is  evidenced  by  a  tendency 
to  the  deposition  of  fat. 


778  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

When  the  castration  is  performed  on  an  adult  man,  the  above  changes 
in  the  sexual  characteristics  are  of  course  not  so  evident,  although  the 
prostate,  etc.,  atrophy.  The  effect  on  the  metabolic  functions  is,  how- 
ever, very  marked,  there  being  a  striking  tendency  to  increased  forma- 
tion of  fat.  It  is  interesting  that  accompanying  this  there  should  usually 
occur  a  lowering  of  the  assimilation  limit  for  carbohydrate,  so  that  glyco- 
suria is  very  readily  induced.  "We  can  not  assume,  therefore,  as  Cush- 
ing  has  done  in  the  case  of  hypopituitarism,  that  the  fat  deposition  is 
attendant  upon  an  improper  combustion  of  carbohydrate. 

These  remarkable  effects  of  castration  have  naturally  prompted  ob- 
servers to  study  the  influence  of  injection  of  testicular  extract  on  the 
development  of  sexual  characteristics  in  different  animals,  but  the  re- 
sults have  in  general  been  considered  to  be  negative  in  character. 

The  Female  Generative  Organs 

It  is  well  known  that,  besides  their  function  in  producing  ova,  the 
ovaries  also  produce  autacoids  that  have  to  do  not  only  with  the  fixa- 
tion of  the  embryo  in  utero,  but  also  with  the  changes  that  occur  during 
pregnancy  in  the  maternal  organism.  It  is  however  at  present  uncertain 
as  to  where  these  autacoids  are  produced  in  the  ovary.  The  two  most 
likely  sources  are  the  stroma  cells  and  the  corpus  luteum.  In  the  stroma 
of  the  ovary  of  certain  animals,  groups  of  cells  have  been  described 
having  a  different  appearance  from  those  of  ordinary  stroma  cells. 
They  have  been  called  the  interstitial  cells  of  the  ovary,  and  are  believed 
to  be  analogous  with  the  similar  structures  found  in  the  testicle.  It  is 
possible,  however,  that  these  interstitial  cells  are  nothing  more  than 
cells  derived  from  previous  corpora  lutea.  The  latter  are  formed  by 
proliferation  of  the  follicular  epithelium  which  remains  after  extrusion 
of  the  ovum,  and  by  the  ingrowing  into  the  follicle  of  the  so-called  theca 
cells  and  blood  vessels.  The  fully  developed  corpus  luteum  in  most 
animals  consists  of  cells  arranged  in  trabecule  converging  toward  the 
scar  which  formed  at  the  place  where  the  follicle  had  burst.  The  luteal 
cells,  as  they  are  called,  are  characterized  by  containing  considerable 
quantities  of  lipoid  material. 

That  the  ovary  produces  some  autacoid  is  evidenced  by  both  clinical 
and  experimental  observations.  Thus,  if  both  ovaries  are  removed  in  a 
young  animal  (oophorectomy  or  spaying),  it  is  well  known  that  not 
only  does  the  uterus  fail  to  develop  properly,  but  the  external  changes 
characteristic  of  puberty  in  the  female  fail  to  materialize,  although  act- 
ually the  general  effects  are  not  so  pronounced  as  they  are  in  the  male 
after  castration.  Menstruation  does  not  set  in;  the  mammary  glands  fail 
to  develop ;  and  there  is  a  tendency  for  the  hair  to  grow  as  in  the  male. 


THE   PINEAL   GLAND   AND   THE   GONADS  779 

When  the  operation  is  performed  in  adull  life,  the  changes  arc  not  very 
pronounced,  except  that  menstruation  ceases  and  the  uterus  and  mam- 
mary  glands  atrophy.  Metabolism  also  becomes  altered,  causing  a 
tendency  to  the  deposition  of  Eat,  and  in  the  case  of  the  human  animal  at 
least,  there  is  frequently  evidence  of  menial  disturbance. 

Attempts  to  acquire  more  definite  information  regarding  the  physio- 
logic effects  of  the  ovarian  autacoid  have  recently  been  made  by  Schafer 
and  [tagaki.60  Extracts  were  prepared  From  the  corpus  luteum  or  Graafian 

follicles  or  from  the  hilum  ovariae,  and  observations  were  made  on  the 
effect  produced  on  the  behavior  of  the  chief  forms  of  unstriated  muscle 
by  adding  the  extracts  to  isolated  preparations  of  uterus  or  intestine 
or  by  injecting  the  extracts  into  animals.  Applied  to  the  isolated  prepa- 
rations, extract  of  follicular  tissue  or  of  liquor  folliculi  "was  found  to 
increase  the  force  and  rate  of  the  rhythmic  contractions  of  the  uterus  as 
well  as  its  tone,  whereas  inhibition  was  produced  when  extract  of  the 
hilum  was  used.  Extract  of  corpus  luteum,  when  injected  into  the 
veins,  was  found  to  cause  the  uterus  to  increase  its  contraction  or  if 
quiescent  to  begin  contracting.  It  was  further  noted  that  extracts  of 
hilum  caused  a  fall  in  arterial  blood  pressure,  whereas  those  of  corpus 
luteum  had  little  or  no  effect.  It  would  appear  from  these  observations 
that  the  extracts  contain  two  different  autacoids,  one  having  a  hormonic 
and  the  other  a  chalonic  action  on  plain  muscular  fiber. 

Extract  of  corpus  luteum  when  intravenously  injected  also  stimulates 
the  outpouring  of  the  milk  from  the  mammary  glands,  although  not  so 
markedly  so  as  extract  of  pituitary  gland.  This  pituitary-like  action  is 
not  obtained  with  extracts  of  ovary  that  do  not  contain  corpora  lutea. 
Besides  being  concerned  in  the  outpouring  of  milk,  corpus  luteum  has 
also  been  shown  to  be  related  in  some  way  to  the  development  of  the 
mammary  gland  during  pregnancy.  These  glands  become  developed  in 
young  virgin  rabbits  after  the  continuous  administration  for  a  month 
or  so  of  extract  of  corpus  luteum,  and  they  also  develop  in  unimpreg- 
nated  animals  when  the  corpus  luteum  is  made  to  develop  by  artificial 
means  such  as  puncturing  the  Graafian  follicle.  Furthermore,  destruc- 
tion of  the  corpora  lutea  in  a  pregnant  rabbit  arrests  development  of 
the  mammary  glands.  The  corpus  luteum  has  also  an  important  func- 
tion in  connection  with  the  formation  of  the  uterine  decidua  and  the 
fixation  of  the  embryo.  Thus,  after  destruction  of  the  corpus  luteum  at 
an  early  period  in  pregnancy,  the  embryo  fails  to  become  adherent  to 
the  uterus. 


780  THE    ENDOCRINE    ORGANS,    OR    DUCTLESS   GLANDS 

DUCTLESS  GLANDS  REFERENCES* 

(Monographs) 

ssvincent,  Swale:     Internal  Secretions  and  the  Ductless  Glands,  Ed.  Arnold,  London. 
soBiedl:      The  Internal  Secretory  Organs.  Win.  Wood  &  Co.,  1913. 

coSchafer,  Sir  E.  A.:     The  Endocrine  Organs,  Longmans,  Green  &  Co.,  New  York  and 
London,  191G. 

(Original  Papers) 

eiFulk,  M.  E.,  and  Macleod,  J.  J.  E.:     Am.  Jour.  Physiol.,  1916,  xl,  21. 
62Folin,  O.,  Cannon,  W.  B.,  and  Denis,  W.:     Jour.  Biol.'  Chem.,  1913,  xiii,  447. 
G3Cannon,  W.  B.,  and  Grav,  H.:     Am.  Jour.  Physiol.,  1914,  xxxiv,  232;  also  with  Men- 

denhall,  W.  L.:     Ibid.,  243  and  251. 
64Hartman,  T.  H.,  and  others:     Am.  Jour.  Phvsiol.,  1915,  xxxviii,  433;  ibid.,  1917,  xliii, 

311;  ibid.,  xliv,  353;  ibid.,  1918,  xlv. 
c^Hoskins,  R.  G. :     Am.  Jour.  Physiol.,  1912,  xxix,  303;  Jour.  Pharm.  and  Exp.  Therap., 

1911,  iii,  93;  Am.  Jour.  Phvsiol.,  1915,  xxxvii,  471;  ibid.,  191(5,  xli,  513. 
ceStewart,  G.  N,  and  Eogoff,  J.  M.:    Jour.  Lab.  and  Clin.  Med.,  1918,  iii,  209.    See  full 

bibliography  by  Rogoff  in  this  paper. 
eTElliott,  T.  R.:     Jour.  Phvsiol.,  1912,  xliv,  374. 

csStewart,  G.  X.:     Jour.  Exp.  Med.,  1911,  xiv,  377;  ibid.,  1912,  xv,  547;  ibid.,  xvi,  502. 
69Stewart,  G.  N,  Rogoff,  J.  M.,  and  Gibson:     Jour.  Pharm.  and  Exper.  Therap.,  1916, 

viii,  205. 
roMeltzer,  S.  J.:     Deutsch.  mod.  Wchnschr.,  1909,  xiii. 
nstewart,  G.  N.:     Jour.  Exper.  Med.,  1912,  xv,  547. 
"Cannon,  W.  B.,  et  al.:     Am.  Jour.  Physiol.,  1911,  xxviii,  64;  ibid.,  1914,  xxxiii,  356; 

also  Bodily  Changes  in  Hunger,  Four,  and  Ra^e,  Appleton,  1915. 
"Cannon,  W.  B.,*  and  Cattell,  McKeen :     Am.  Jour.  Physiol.,  1916,  xli,  74. 
viMacleod,  J.  J.  R.,  and  Pearce,  R,  G. :     Am.  Jour.  Physiol.,  1912,  xxix,  419. 
"Marine,  D. :     Personal  communication. 
"Marine,  D.:     Jour.  Exper.  Med.,  1914,  xix,  89. 
"Marine,  D.,  and  Lenhart,  C.  II.:     Jour.  Exper.  Med.,  1910,  xii,  311;   ibid.,  1911,  xiii, 

455;   also  Bull.  Johns  Hopkins  Hosp.,  1910,  xxi,  95. 
"Marine,  D.,  and  Kimball,  O.  P.:     Jour.  Lab.  and  Clin.  Med.,  1917,  iii,  41. 
"Kendall,  E.  C:     Boston  Med.  and  Surg,  .lour.,  1916.  175.  557:  also  Proc.  Am.  Physiol. 

Soc,  Am.  Jour.* Physiol.,  1918,  xliv. 
sopaton,   Noel   and   FiDiay:     Quart,   Jour.   Exp.   Physiol.,   1917,   x,   203.     Paton,    Noel, 

Finlav  and  Watson,  A.:     Ibid.,  233,  243,  315,  and  377. 
siMacCallum,  W.  G.,  etc.:     Jour.  Exper.  Med.,  1909,  xi,  118;   ibid.,  1913,  xviii,  646: 

Jour.  Pharm.  and  Exper.   Therap..   1911,  ii,  421. 
s^Cushing,  Harvey:     The  Pituitary  Body  and  Its  Disorders,  J.  B.  Lippincott  Co.,  1912. 
ssHorsley,  V.:     Brit.  Med.  Jour.,  1885,  i,  111. 
siRobertson,  Brailsford,  and  Ray,  L.  A.:     Jour.  Biol.  Chem..  1916,  xxiv,  347,  363,  385. 

397,  409. 
ssClark,  L.  N.:     Jour.  Biol.  Chem.,  1915,  xxii,  485. 


"The   numbering  is   in   continuation   with  that  for  metabolism. 


PART,  IX 
THE  CENTRAL  NERVOUS  SYSTEM 


CHAPTER  LXXXVT 
THE  EVOLUTION  OP  THE  NERVOUS  SYSTEM 

The  nervous  system  of  the  higher  animals  consists  of  the  nerve  cen- 
ters, and  the  nerves  with  their  various  interconnecting  tracts.  The 
nerve  tract  and  centers  are  located  mainly  in  the  spinal  cord  and  brain, 
where,  by  their  interlacement,  they  form  an  extremely  complex  struc- 
ture. The  exact  position  of  the  centers  and  the  course  and  connections 
of  the  tracts  with  the  centers  are  problems  which,  under  the  title  of 
neurology,  have  during  recent  years  been  contributed  to  more  particu- 
larly by  the  anatomist  and  the  pathologist.  The  information  thus 
gathered  tells  us  the  possible  tract  or  tracts  of  nerve  fibers  through  which 
the  various  centers  may  communicate  either  with  one  another  or  with 
the  structures  outside  the  central  nervous  system  upon  which  they 
act.  Since  each  of  these  centers  may,  however,  be  played  upon  by  in- 
fluences coining  from  different  regions  of  the  body,  it  is  evident  that  there 
must  remain,  as  an  equally  important  aspect  of  the  subject,  the  investi- 
gation of  the  means  by  which  the  various  available  centers  and  tracts  are 
brought  into  communication  and  action  at  the  proper  time.  In  other 
words,  we  must  investigate  the  functional  uses  of  the  available  paths. 
'  We  may  compare  the  central  nervous  system  with  a  telephone  system, 
the  exchanges  representing  the  nerve  centers,  and  the  wires  the  nerve 
trunks.  Any  incoming  wire  may  be  connected  by  the  operator  with 
any  outgoing  wire,  but  a  knowledge  of  how  each  wire  runs  does  not  tell 
us  under  what  conditions  the  various  wires  will  be  connected  for  trans- 
mission of  messages.  It  is  the  same  with  the  nervous  system ;  the  neurolo- 
gist can  tell  us  how  the  tracts  and  centers  run,  but  not  the  conditions 
under  which  they  may  act  together.  This  it  is  the  duty  of  the  physiologist 
to  ascertain. 

Since  it  is  the  degree  of  development  of  the  central  nervous  system 
which  determines  an  animal's  position  in  the  evolutionary  scale,  much 
information  concerning  the  relative  importance  of  the  various  parts  of 

781 


782  THE    CENTRAL    NERVOUS    SYSTEM 

it  can  be  gleaned  from  a  survey  of  the  conditions  under  which  the 
nervous  system  makes  its  appearance  in  the  lowest  forms  of  animal 
life.  In  the  case  of  unicellular  organisms,  such  as  the  ameoa,  the  ap- 
plication of  a  stimulus  to  the  surface  causes  a  movement,  because  the 
protoplasm  of  the  organism  possesses,  among  its  other  properties,  those 
of  excitability,  conductivity  and  contractility.  In  the  case  of  multicel- 
lular organisms,  on  the  other  hand,  some  cells  are  set  aside  and  spe- 
cialized for  the  assimilation  of  food,  others  for  movement,  others  to 
receive  stimuli  from  the  outside,  and  yet  others  to  compose  the  tougher 
tissues  which  protect  the  surface  of  the  animal  from  injury.  This  loca- 
tion of  specific  function  in  specialized  groups  of  cells  makes  it  necessary, 
for  the  welfare  of  the  organism  as  a  whole,  that  some  means  of  com- 
munication should  be  provided  between  the  distant  parts  of  the  animal, 
for  otherwise  the  cells  which  are  occupied  in  absorbing  food  would  be 
unable  to  move  away  or  be  protected  from  harm  when  some  destructive 
agency  approached  them,  and  indeed  the  moving  (muscle)  cells  could 
never  know  when  the  welfare  of  the  organism  as  a  whole  demanded  that 
they  should  become  active. 

It  is  probable  that,  in  some  of  the  lower  organisms,  the  messages  trans- 
mitted from  one  group  of  cells  to  the  others  are  carried  by  chemical 
substances  present  in  the  circulating  fluid — hormones,  as  they  are  called 
(page  729).  For  the  quick  adaptation  that  is  necessary  in  the  struggle 
for  existence,  however,  such  hormones  are  usually  too  slow  in  bringing 
about  the  response,  and  very  early  in  the  evolutionary  scale  we  find  that  cer- 
tain cells  become  differentiated  for  this  special  purpose.  The  cells  thus 
specialized  constitute  the  nervous  system,  their  differentiation,  as  would 
be  expected,  being,  however,  antedated  by  that  of  the  cells  that  form  the 
muscular  tissues.  In  the  sponges,  for  example,  muscle  cells  become 
developed  from  ameboid  epithelium  and  from  a  layer  underneath  the 
external  epithelium.  These  muscle  cells  contract  slowly  so  as  to  cause 
opening  and  closing  of  the  small  mouths,  or  oscula,  on  the  surface  of 
the  sponge  in  response  to  movements  in  the  sea  water.  They  are  in- 
dependent of  any  nervous  structures. 

In  certain  Coelenterates  the  muscle  cells  respond  a  little  more  quickly 
than  in  the  sponges,  and  this  greater  efficiency  is  found  to  be  dependent 
upon  the  appearance  of  a  localized,  very  primitive  nervous  system1. 
This  nervous  system  consists  of  specially  modified  epithelial  cells,  or 
receptors,  sending  branches  from  their  inner  ends,  which  either  come  in  con- 
tact with  the  muscle  cells,  or  effectors,  or  become  interlaced  so  as  to  form  a 
network.  In  the  region  between  the  receptors  and  the  effectors  the  net- 
work at  first  serves  merely  as  a  structure  whereby  the  entire  muscula- 
ture of  the  animal  can  be  brought  into  harmonious  action  from  a  single 


Till;    EVOLUTION   OF   TIIK   NERVOUS   SYSTEM 


783 


point  on  the  surface,  as,  for  example,  in  the  case  of  the  sea  anemone 
(No.  2  of  Fig.  201).  In  the  jellyfish,  which  in  contrast  to  the  sea  anemone 
is  a  free  moving  animal,  we  find  that  the  receptors  are  more  highly  special- 
ize and,  therefore,  much  more  sensitive,  and  that  the  impulses  which  they 
receive  are  transmitted  to  a  more  definite  nerve  network,  capable  not  only 
of  conveying  the  excitatory  process  from  one  part  of  the  animal  to  another, 


Spentje 


Sea  anemone 


gang 


Simple  form  In 
earthworm 


J  6  Addition  of 

association  neurons 
in  earthworm 


9anS\ 


Fig.  201. — Diagram  to  show  gradual  evolution  of  nervous  system  from  an  epithelial  cell  (e) 
and  muscle  fiber  (m)  in  the  sponge  (/)  to  a  specialized  epithelial  cell  or  receptor  O)  and  muscle 
cell  in  the  sea  anemone  {2) ;  then  to  a  receptor  and  motor  neuron  joining  in  a  ganglion  {Gang.), 
in  simple  form  seen  in  the  earthworm  (3).  Most  of  the  ganglia  in  this  and  other  segmented 
invertebrates    show    also    the    internuncial    or    association    neurons    as    indicated    in    4. 

but  also  of  imprinting  on  the  impulse  a  characteristic  rhythmic  activity 
which  brings  about  the  contraction  of  the  bell  and  the  swimming  movement 
of  the  animal.  The  network  now  assumes  the  function  of  an  adjuster 
as  Avell  as  a  transmitter  of  impulses. 

So  far  the  adjuster  is  an  extremely  simple  structure,  and  it  is  possible 
that  the  effector  and  receptor  organs  are  directly  connected  by  fibers 
running   through   it.     When   we   come   to    the   segmented   invertebrates 


784 


THE    CENTRAL    NKRVOUS    SYSTEM 


(such  as  the  earthworm,  crayfish,  lobster,  etc.,)  much  more  definite  spe- 
cialization of  the  adjuster  occurs,  for  now  this  intermediate  nervous  tis- 
sue becomes  collected  into  so-called  ganglia,  a  pair  existing  for  each 
segment  and  the  various  pairs  being  connected  by  definite 
nerve  structures,  constituting  the  ganglion  chain.  It  is  in 
this  group  of  animals  that  we  have,  for  the  first  time,  def- 
inite evidence  of  the  existence  of  the  neuron,  which  may  be 
considered  as  the  elementary  unit  of  which  the  nervous  sys- 
tem of  all  the  higher  animals  is  built.  A  neuron  may  be 
either  sensory  or  motor,  and  in  both  eases  it  consists  of 
a  cell  with  a  nucleus,  one  long  process,  called  the  axon, 
and  several  short  branching  processes,  called  the  den- 
drites. The  axon  in  its  course  may  give  off  a  branch, 
or  more,  at  right  angles,- — these  are  sometimes  called 
collaterals, — and  at  its  end  it  may  break  up  into  very  fine 
branches  called  a  synapsis.  In  a  sensory  neuron  the  im- 
pulse is  transmitted  from  the  end  of  the  axon  to  the 
nerve  cell,  whereas  in  a  motor  neuron  it  is  transmitted 
in  the  opposite  direction  from  the  cell  to  the  end  of  the 
axon  (Fig.  203). 

The  simplest  arrangement  of  sensory  and  motor  neu- 
rons to  constitute  the  nervous  system  is  seen  in  the 
earthworm,  in  which  it  forms  the  simplest  type  of  reflex 
arc  (Fig.  201,  No.  3).  The  sensory  neuron  has  its  cell 
body  in  the  skin,  and  its  axon  proceeds  to  one  of  the 
segmental  ganglia,  in  which  are  large  nerve  cells  whose 
thick  axons  pass  out  from  the  ganglion  as  motor  fibers 
to  the  muscles  of  the  body  wall.  The  dendrites  of  the 
motor  neuron  and  the  branching  of  the  termination  of 
the  sensory  neuron  cause  a  very  fine  interlacement  of 
nerve  fibers  in  the  ganglia,  forming  a  network  known 
as  the  neuropile.  The  sensory  impulse,  on  reaching  the 
ganglion,  is  transmitted  by  the  synapsis  to  the  den- 
drites, probably  without  the  fibers  actually  joining  to- 
gether; that  is,  the  nerve  impulses  pass  from  the  one 
to  the  other  set  of  branches  by  contact  rather  than  by 
transmission  through  continuous  tissue. 

By  such  an  arrangement  it  is  evident  that  the  nervous 
apparatus  in  each  segment  could  cause  a  contraction  of 
the  muscles  of  its  own  neighborhood,  but  that  a  stimulus  applied  to  one  re- 
ceptor would  be  incapable  of  calling  forth  a  contraction  of  the  muscles. of  a 
far  distant  segment,  much  less  a  coordinated  contraction  of  the  musculature 


Fig.  20-'.— Dia- 
gram of  nervous 
system  of  seg- 
mented inverte- 
brate; a.  supra- 
esophageal  g  a  n- 
glion;  b,  subeso- 
phageal  ganglion; 
nc,  esophagus  or 
gullet. 


THE   EVOLUTION    OF   THE    NERVOUS   SYSTEM 


78r> 


of  the  whole  animal  such  as  would  be  required  for  Locomotion.  To  render 
this  possible  it  is  necessary  that  some  means  of  communication  become  es- 
tablished between  the  different  segmental  ganglia.  This  is  effected  by 
association  neurons,  each  of  which,  as  the  name  implies,  consists  of  a  nerve 
cell  with  its  dendrites  located  in  one  ganglion  and  of  an  axon,  which  passes 
to  the  next  or  even  to  some  more  distant  ganglion,  where  it  ends  by 
synapsis.  The  important  point  to  note  is  that  these  association  neurons 
do  not  leave  the  central  nervous  system;  they  merely  connect  various 
ganglia. 

So  far  the  ganglia  of  each  segment  are  of  equal  importance,  but  if 
we  examine  further  we  shall  find  that  at  the  head  end  of  the  animal 
several  of  the  ganglia  become  fused  together  to  form  a  larger  ganglion, 


Fig.   203. — Schema  of  simple  reflex  arc;   r,   receptor  in  an  epithelial   membrane;   a,   afferent   fiber;   s, 
synapsis;    c,    nerve   cell    of   center;    e,    efferent    fiber;    m,    effector    organ. 

which  lies  just  behind  the  gullet,  and  from  which  fibers  proceed  around 
the  gullet  to  unite  in  front  of  it  in  another  large  ganglion,  which  usually 
shows  three  lobes.  These  larger  ganglia  receive  afferent  nerve  fibers 
from  the  closely  adjacent  primitive  sense  organs  for  sight,  sound  and 
smell,  from  structures,  that  is,  that  are  really  highly  specialized  recep- 
tors. The  cells  of  the  retina  and  ear  have  been  made  capable  of  reacting 
to  impulses  of  light  or  sound  instead  of  those  of  pain,  touch  or  tempera- 
ture, to  which  the  receptors  of  the  integument  are  especially  sensitized. 
They  are  distance  receptors  (projicient  receptors),  and  it  is  evident  that 
the  nerve  reflexes  with  which  they  are  concerned  are  of  a  higher  order 
than  those  located  in  the  segmental  ganglia  themselves. 

Some  of  the  neurons  of  the  head  ganglia  are  merely  motor  and  act  on 
the  muscles  of  the  head  end  of  the  animal,  but  others  are  purely  associa- 


786  THE    CENTRAL    NERVOUS    SYSTEM 

tion  neurons  and  proceed  down  the  ganglion  chain  to  terminate  by- 
synapses  in  one  or  other  of  the  segmental  ganglia.  These  association 
neurons  exercise  a  dominating  influence  over  the  activities  of  the  seg- 
mental ganglia,  so  that  they  may  determine  the  response  of  the  animal 
when  its  safety  is  threatened  by  some  approaching  enemy.  When,  for 
example,  the  stimulus  produced  by  some  sight  or  sound  of  an  approach- 
ing enemy  is  received  by  the  head  ganglia,  these  will  transmit  impulses 
down  the  ganglion  chain  which  so  influence  the  various  nerve  cells  of 
this  chain  as  to  produce  in  all  of  them  a  coordinated  action  for  the  pur- 
pose of  removing  the  animal  from  danger.  Even  should  some  local 
stimulant  be  acting  on  one  or  more  of  the  segments,  the  response  may  be 
inhibited  on  account  of  stimuli  meanwhile  transmitted  by  way  of  asso- 
ciation neurons  from  the  large  head  ganglia ;  in  other  words,  the  part 
controlled  by  the  segmental  ganglia  becomes  subservient  to  the  whole 
through  the  dominating  control  of  the  head  ganglia. 

This  illustrates  the  beginnings  of  the  integration  of  the  nervous  system; 
and  as  we  pass  to  the  study  of  the  higher  animals,  we  shall  see  that  this 
integration  becomes  more  and  more  complicated,  and  that,  as  it  does  so, 
the  nerve  centers  acquire  the  power  of  storing  away  the  impressions  they 
receive,  which  they  may  afterwards  apply  to  regulate  the  reflex  response. 
Thus  memory  and  volition  come  to  find  their  place  in  the  nervous  inte- 
gration of  the  animal.  The  afferent  stimulus  arriving,  let  us  suppose, 
at  nerve  cells  controlling  the  movement  of  the  leg,  may  fail  to  cause 
a  response  of  the  corresponding  muscles  because  of  impulses  meanwhile 
transmitted  by  association  neurons  from  higher  memory  centers,  for 
the  animal  may  have  learned  by  experience  that  sueh  a  movement  as  the 
local  stimulus  would  in  itself  call  forth  is  opposed  to  its  own  best  in- 
terests. This  experience  will  have  been  stored  away  in  memory  nerve 
centers,  so  that,  whenever  the  local  stimulus  is  repeated,  impulses  are 
discharged  from  the  memory  centers  to  the  local  nerve  centers,  and 
the  reflex  response  does  not  occur,  or  is  much  modified  in  nature.  For 
storing  away  these  memories  and  for  related  psychologic  processes  of 
volition,  etc.,  the  anterior  portions  of  the  nervous  system  in  higher  ani- 
mals become  very  highly  developed  so  as  to  constitute  the  brain,  and 
the  simple  chain  of  ganglia  of  the  invertebrates  is  replaced  by  the 
spinal  cord. 

As  we  ascend  the  scale  of  the  vertebrates,  the  brain  becomes  more 
and  more  developed,  until  in  the  higher  mammalia,  such  as  man,  very 
few  reflex  actions  can  occur  independently  of  the  higher  centers  which 
are  located  in  it.  The  reflex  arc  now  involves,  not  one  nerve  center, 
but  several,  and  of  these  the  most  important  are  located  in  the  brain. 
There  is  thus  no  essential  difference  in  the  general  nature  of  integra- 


THE    EVOLUTION   OF   THE    NERVOUS   SYSTEM  787 

tion  in  the  nervous  system  of  the  lower  as  compared  with  the  higher 
animals,  but  there  is  a  very  distinct,  morphologic  difference:  in  the  lower 
or  invertebrate  animals  the  ganglion  nerve  chain  is  ventral  to  the  alimen- 
tary canal,  whereas  in  the  higher  or  vertebrate,  the  spinal  eord,  which 
takes  the  place  of  the  ganglia,  is  dorsal  to  the  alimentary  canal.  In  both 
groups  the  head  ganglia  are  dorsal  to  the  alimentary  canal,  but  in  the 
vertebrates  these  become  much  more  definite  in  structure,  and  constitute 
the  brain.  This  morphologic  difference  between  vertebrates  and  inverte- 
brates is  probably  not  so  fundamental  as  at  first  sight  it  may  appear  to 
be,  for,  as  Gaskell  has  shown,  it  is  possible  that  the  alimentary  canal  of 
the  invertebrates  is  really  homologous  with  the  central  canal  of  the 
spinal  cord  and  the  ventricles  of  the  brain  of  the  vertebrates.  Accord- 
ing to  this  observer,  what  has  really  happened  in  the  latter  group  of 
animals  is  that  the  ganglia  have  grown  up  so  as  to  surround  the  alimen- 
tary canal  and  so  constitute  a  continuous  structure,  a  new  alimentary 
canal  being  meanwhile  provided  by  the  enclosure  of  a  space  as  a  result 
of  ventral  downgrowth  of  the  body  walls.  Although  this  view  has  not 
been  generally  accepted  by  biologists,  there  is  no  inherent  reason  why  it 
should  not  be  accepted.  It  is  no  more  to  be  wondered  at  than  the  well- 
known  fact  that  a  new  respiratory  system  becomes  developed  in  the 
passage  from  aquatic  to  land  amphibians. 

The  fibers  of  the  sensory  neurons  in  vertebrates  are  collected  together 
to  form  the  posterior  roots  of  the  spinal  cord,  and  the  cell  bodies  of  these 
neurons  are  located  not  on  the  surface,  as  in  invertebrates,  but  in  the 
posterior  root  ganglia,  the  cells  being  connected  to  the  fibers  by  T-shaped 
junctions.  The  olfactory  nerve  is  the  only  one  in  the  higher  vertebrates 
which  retains  its  primitive  condition. 

In  the  vertebrate  animals  the  spinal  member  in  the  integration  of  the 
central  nervous  system  is  the  motor  neuron,  the  fibers  being  collected  in 
the  anterior  roots.  Toward  the  cell  of  this  neuron  impulses  are  transmitted, 
not  only  from  the  segment  in  which  it  is  itself  located,  but  by  way  of  as- 
sociation neurons  from  other  segments  or  from  far  distant  parts  of  the 
central  nervous  system.  In  other  words,  this  motor  neuron  may  transmit 
impulses  which  cause  the  muscles  to  perform  local  independent  move- 
ments, which  are  coordinated  with  those  of  adjacent  segments  and  which 
may  be  of  widely  varying  types.  The  motor  neuron  has  therefore  very 
appropriately  been  called  the  final  common  path,  and  it  will  be  one  of  our 
main  objects  later  to  show  the  conditions  under  which  several  different 
competing  influences  may  obtain  possession  of  this  path. 


CHAPTER  LXXXVIl 

THE  PROPERTIES  OF  EACH  PART  OF  THE  REFLEX  ARC 

Having  briefly  traced  the  physiologic  development  of  the  nervous  sys- 
tem, we  are  prepared  to  consider  in  greater  detail  the  peculiar  function 
of  each  of  the  parts  which  enter  into  the  formation  of  the  reflex  arc. 

THE  RECEPTOR 

With  the  advance  in  animal  organization  is  associated  the  development 
of  the  ability  to  appreciate  and  discriminate  between  external  phe- 
nomena, special  organs  called  receptors  being  evolved  to  receive  the 
stimuli  which  these  occasion.  Those  receptors  which  are  distributed 
over  the  skin  of  the  animal  are  called  external  or  cxteroceptors,  and  are 
especially  adapted  to  react  to  such  stimuli  as  temperature,  pressure, 
and  pain,  but  at  the  fore  end  of  the  animal  certain  receptors  become  more 
highly  specialized  so  as  to  react  to  stimuli  coming  from  a  distance — 
that  is,  to  stimuli  that  are  not  produced  by  contact  of  external  objects 
with  the  surface  of  the  animal.  These  specialized  receptors — sometimes 
called  projicient — include  the  eye,  the  ear,  and  the  olfactory  epithelium. 
Receptors  are  also  provided  in  the  interior  of  the  organism  for  the  pur- 
pose of  receiving  stimuli  dependent  upon  the  activities  of  the  organism 
itself.  They  may  be  called  internal  receptors,  and  we  may  further  dis- 
tinguish two  groups  of  them — namely,  those  which  come  from  the  sur- 
faces of  the  mucous  membranes  and  those  which  come  from  the  sub- 
stance of  the  various  organs  and  tissues  themselves,  as,  for  example, 
from  the  substance  of  muscle  or  tendon. 

A  receptor  may  be  defined  in  a  general  way  as  a  mechanism  in  which 
some  particular  kind  of  stimulus  produces  changes  that  result  in  the 
excitation  of  the  nerve  fiber  with  which  the  receptor  is  connected,  al- 
though the  stimulus  in  itself  is  incapable  of  exciting  the  nerve  fiber.  In 
other  words,  as  Sherrington  puts  it,  the  receptor  has  the  threshold  of 
its  excitability  raised  to  every  kind  of  stimulus  save  one,  toward  which 
it  is  lowered.  A  nerve  fiber,  for  instance,  responds  to  every  kind  of 
stimulus  approximately  equally;  a  receptor  will  also  respond  to  these 
same  stimuli,  but  with  great  inequality,  since  each  receptor  is  specialized 
to  react  to  one  kind  of  stimulus  and  to  others  only  when  these  are  very 
strong. 

788 


THE    PROPERTIES    OF    EACH    I'ART    OF    THE    REFLEX    ARC  789 

It  is  often  a  difficult  matter  to  determine  just  exactly  what  it  is  in 
the  nature  of  the  stimulus  that  makes  it  capable  of  affecting  one  receptor 
and  not  another;  for  example,  it  is  often  merely  a  question  of  the  rate 
of  vibration  of  the  stimulus.  Light  and  heat  rays  are  both  due  to 
vibration  of  the  ether  -which  fills  space.  When  these  vibrations  are 
slow,  they  stimulate  receptors  that  have  been  specialized  for  apprecia- 
tion of  temperature,  but  when  they  are  rapid  and  exist  as  rays  of  light, 
they  no  longer  affect  the  temperature  receptors  but  only  the  highly  spe- 
cialized receptors  of  the  retina.  Similar  vibrations  of  the  air  in  place 
of  the  ether  cause  sound  and  stimulate  the  auditory  receptors.  It  is 
quite  likely  that  the  receptors  in  different  groups  of  animals  are  attuned 
to  react  to  different  rates  of  vibration.  For  example,  a  cat  can  hear 
higher  pitched  notes  than  man,  and  it  is  possible  that  the  retinas  of 
some  animals  respond  to  rays  vibrating  with  a  different  frequency  from 
those  to  which  the  retina  of  man  is  adapted.  In  this  connection  it  is  of  in- 
terest to  note  that  the  touch  receptors  of  the  skin  respond  so  promptly 
to  stimulation  that  one  hundred  vibrations  of  a  tuning  fork  per  second 
can  be  felt  as  separate  stimuli,  whereas  to  the  ear  at  this  frequency  the 
fork  emits  a  continuous  note.  The  receptors  of  touch  are  therefore  more 
prompt  in  their  response  than  the  receptors  of  the  auditory  nerve. 

"When  once  the  receptor  has  been  stimulated,  the  impulse  passes  and 
is  transmitted  to  the  nerve  centers,  where  it  is  translated  into  a  par- 
ticular sensation.  The  conditions  are  really  not  unlike  those  which  ob- 
tain in  the  case  of  the  various  physical  instruments  used  to  receive  and 
convert  into  the  electric  current  stimuli  of  heat,  light,  chemical  energy. 
etc.  The  receiver  required  to  bring  about  this  transformation  must  be 
especially  constructed  in  each  case,  that  for  light  being  the  actinometer, 
that  for  motion  the  dynamo,  that  for  heat  the  thermopile,  and  that  for 
chemical  energy  the  concentration  cell.  Each  of  these  physical  instru- 
ments may  be  considered  as  a  specialized  receptor  for  the  purpose  of 
producing  an  electric  current  out  of  other  forms  of  energy. 

In  accepting  the  above  analogy  we  must  not  fail  to  bear  in  mind 
that  very  feeble  stimuli  are  often  able  to  set  in  operation  nerve  impulses 
that  are  as  potent  as  those  produced  by  much  stronger  stimuli.  Here 
again,  we  have  a  physical  analogue  in  the  case  of  relay  currents,  in 
which  a  feeble  electric  current  may  operate  to  complete  the  circuit  from 
independent  sources  of  electric  discharge  and  thus  set  in  motion  a  much 
larger  amount  of  energy. 

These  general  considerations  of  the  nature  of  a  receptor  naturally 
lead  us  to  the  law  of  the  specific  properties  of  nerve,  which  is  to  the 
effect  that,  however  excited,  each  nerve  of  special  sense  gives  rise  to 
its  own  peculiar  sensation.    Thus,  in  whatever  way  the  chorda  tympani 


790  THE    CENTRAL    NERVOUS    SYSTEM 

nerve  is  stimulated  (chemically,  mechanically  or  electrically)  during  its 
passage  across  the  tympanum,  the  sensation  evoked  is  that  of  taste. 
And  so  with  the  receptor;  whatever  the  means  by  which  it  is  excited, 
whether  by  the  particular  kind  of  stimulus  for  which  it  is  adapted  or  by 
excessive  intensities  of  other  stimuli,  excitation  always  evokes  the  same 
sensation.  If  the  optic  nerve  or  retina  is  mechanically  stimulated,  as 
by  pressure  against  the  outer  canthus  of  the  eye  or  by  an  electric  cur- 
rent, the  sensation  is  that  of  light.  Applying  these  facts  to  less  well- 
known  receptors,  such  as  those  of  heat  and  cold,  it  is  interesting  to  note 
that  stimulation  of  a  "cold  spot"  by  extreme  heat  or  by  mechanical 
or  electrical  stimuli  brings  out  the  sensation  of  cold. 

Properties  of  Epicritic  and  Protopathic  Receptors 

A  valuable  groupinrj  of  receptors  of  the  skin  has  been  demonstrated  by 
Head  and  his  pupils  by  experiments  on  himself.  Head  found  after  sec- 
tion of  the  skin  nerves — of  the  radial  nerve,  for  example — that  deep 
pressure  and  pain  were  still  present  in  the  area  supplied  by  the  nerve, 
indicating  that  these  deep  sensations  are  carried  by  the  sensory  fibers 
present  in  the  muscular  nerves.  In  such  a  paralyzed  sensory  region  the 
power  of  general  localization  is  fairly  good,  although  light,  touch,  tem- 
perature and  superficial  pain  are  entirely  absent  in  the  overlying  skin. 

In  the  case  of  the  fingers  the  nerves  of  deep  sensibility  run  in  the  ten- 
dons of  the  finger  muscles,  so  that  after  severance  of  the  cutaneous 
nerves  and  tendons  of  the  hand,  all  sensibility  is  gone. 

During  the  regeneration  of  the  cut  nerve  the  cutaneous  sensations  re- 
appear at  two  periods:  one  group,-  called  the  protopathic,  begins  to  ap- 
pear in  from  seven  to  twenty-six  weeks,  whereas  the  other,  called  epicritic , 
does  not  fully  appear  for  one  or  two  years.2  The  protophatic  sensations 
are  of  a  distinctly  lower  order  than  the  epicritic.  When  they  alone  are 
present,  there  is  the  sensation  of  pain,  but  not  that  of  fine  touch;  tem- 
perature sensations  are  felt  when  extreme  degrees  of  heat  or  cold — above 
38°  C.  or  below  20°  C. — are  applied  to  the  skin,  but  not  for  slight  de- 
grees: the  power  of  discriminating  between  two  points  is  almost  entirely 
absent;  and  the  sense  of  localization  is  very  imperfect.  For  example,  the 
person  will  often  refer  the  point  that  has  actually  been  stimulated  to  a 
neighboring  normal  portion  of  skin.  Protopathic  sensibility  is  more  or 
less  distributed  in  spots,  and  it  is  strongly  "affective"  in  character,  caus- 
ing an  intense  subjective  sensation.  A  stimulus  that  causes  only  moderate 
pain  under  normal  conditions  produces  in  a  "protopathic  area"  a  pain 
that  may  be  intense. 

The  epicritic  sensation,  as  will  be  inferred  from  the  foregoing,  responds 


TIIK    I'KOI'KKTIIIS    OF    KAt'II    1'AltT    OF    THE    REFLEX    ARC 


71)1 


to  finer  grades  of  stimulation.  By  it  we  can  feel  the  lightest  touch  and 
can  discriminate  the. finest  grades  of  temperature  between  26°  and  37°  C. 
The  power  of  localization  of  the  stimulus  and  the  ability  to  discriminate 
between  two  points  also  return  with  epicritic  regeneration. 

In  the  spinal  cord  the  nerve  fibers  carrying  one  kind  of  sensation 
are  grouped  together,  in  the  sense  that  pain  sensations,  whether  deep  or 
protopathic,  run  in  the  same  column  in  the. cord.  Likewise  temperature 
sensations,  whether  protopathic  or  epicritic,  run  together. 

The  Peculiarities  of  Each  of  the  Separate  Sensations 

Temperature. — The  receptors  for  temperature  are  arranged  in  groups, 
some  being  sensitized  for  heat,  others  for  cold.  These  groups  of  receptors 
are  called  heat  and  cold  spots.     They  can  be  very  easily  detected  on  an 


sV 

Fig.   204. — Thermoesthesiometer. 

area  of  skin  by  means  of  a  pointed  hollow  vessel,  through  which  water  is 
made  to  flow  at  a  temperature  a  little  below  or  a  little  above  that  of  the 
skin.  The  instrument  is  called  a  thermo-esthesiometer.  On  a  part  of  the 
skin  where  there  are  no  heat  and  cold  spots,  the  thermo-esthesiometer  will 
elicit  no  sensation  either  of  heat  or  of  cold.  This  is  charted  on  an  outline 
drawing  of  the  part  as  a  neutral  spot.  At  other  places  it  will  call  forth 
a  sensation  of  heat,  indicating  the  presence  of  heat  spots,  or  at  others  a 
sensation  of  cold,  indicating  the  presence  of  cold  spots.  It  will  be  noted 
that  certain  of  the  spots  are  much  more  reactive  than  others,  and  that  those 
of  cold  are  much  the  more  numerous  (see  Fig.  205).  Both  heat  and  cold 
spots  are  most  frequent  at  the  nipples ;  then,  in  order,  come  the  chest,  the 
nose,  the  anterior  surface  of  the  arm,  and  the  abdomen.  They  are  least 
marked  on  the  exposed  surface  of  the  skin,  such  as  the  face,  and  they  are 


792 


THE    CENTRAL   NERVOUS   SYSTEM 


also  very  infrequent  in  the  scalp.  They  are  almost  absent  from  the  mucous 
membranes,  which  explains  why  one  is  able  to  swallow  a  liquid  that  is  too 
hot  for  the  hand. 

The  acuteness  of  the  temperature  sensation,  as  with  all  the  other  cu- 
taneous sensations,  depends  very  much  on  the  condition  of  the  skin, 
being  most  sensitive  when  this  is  at  the  ordinary  temperature,  but  very 
imperfect  when  it  is  either  very  hot  or  very  cold.  There  is  also  very 
marked  adaptation  of  the  sense.  This  can  be  very  well  shown  by  the  simple 
experiment  of  taking  three  vessels  of  water,  one  at  a  moderate  tempera- 
ture, one  very  hot  and  one  very  cold.  If  a  finger  of  one  hand  is  placed 
in  the  hot  water  and  a  finger  of  the  other  in  the  cold,  and  they  are  left 
there  for  a  short  time,  until  the  skin  has  assumed  the  same  temperature 
as  the  water,  and  then  transferred  to  the  lukewarm  water,  the  finger 


Fig.  205. — Cold  spots  (A)  and  heat  spots  (B)  of  an  area  of  skin  of  the  right  hand.  In  each 
case  the  most  intense  sensations  were  experienced  in  the  black  areas,  less  intense  in  the  lined, 
and  least  in  the  dotted.  The  blank  areas  represent  parts  where  no  special  sensation  of  either 
kind    was    experienced.      (From    Goldseheider.) 


transferred  from  the  cold  water  will  feel  hot,  and  that  transferred  from 
the  hot  water  will  feel  cold.  Temperature  sensation  also  produces  a 
marked  positive  after-effect.  Thus,  if  a  cold  coin  is  placed  on  the  fore- 
head and  then  removed,  the  cold  sensation  will  persist  for  some  time  in 
the  area  of  skin  on  which  the  coin  was  laid. 

That  the  receptors  for  heat  and  cold  respond  only  to  one  kind  of 
stimulus,  or  if  to  others,  only  when  these  are  excessive,  can  be  well  il- 
lustrated by  the  experiment  of  touching  a  cold  spot  with  a  very  hot  ob- 
ject: the  sensation  will  be  that  of  cold.  The  hot  object  has  so  pronounced 
a  power  of  stimulation  that  it  has  overstepped  the  threshold  for  heat 
of  the  cold-adapted  receptors.  The  sensation  of  cold  is  elicited  more 
promptly  than  that  of  warmth.     The  distinction  between  a  warm  and  a 


THE   PROPERTIES  OF    EACH   PART   OF   THE    REFLEX    ARC  793 

hot  bath  may  really  depend  on  the  fact  that  in  the  latter  the  cold  spots 
are  stimulated  as  well  as  those  of  heat.  It  is  at  least  interesting  to  note 
that  the  physiologic  reflexes  stimulated  by  either  a  cold  or  a  very  hot 
bath  are  the  same;  thus,  a  rise  of  blood  pressure  and  a  contraction  of  the 
muscles  of  the  skin  occur  in  both  cases. 

The  Touch  Sense. — In  order  to  investigate  the  touch  sense  accurately, 
vim  Prey  has  devised  a  method  of  using  hairs  of  different  thickness  each 
mounted  on  a  different  handle.  The  hair  "which  produces  a  sensation 
of  touch  when  pressed  on  the  skin  so  that  it  just  bends  is  then  similarly 
pressed  on  one  scale  pan  of  a  balance,  and  the  weight  required  in  the 
other  scale  pan  to  hold  the  beam  horizontal  when  the  hair  just  bends,  is 
ascertained.  From  the  diameter  of  the  hair  one  can  then  calculate  how 
many  grams  per  square  millimeter  are  necessary  to  elicit  the  sensation 
of  touch.  The  following  quantitative  results  have  been  obtained  by  ap- 
plying von  Frey's  method  to  different  parts  of  the  body: 

Gm.  per  sq.  mm. 

Tongue  and  nose  2 

Lip    2.5 

Finger  tip  and  forehead 3 

Back  of  finger . . : 5 

Palm  7 

Forearm  8 

Back    of    hand 12 

Calf,  shoulder  16 

Abdomen    26 

Outside   of  thigh 2<5 

Shin  and  sole   28 

Back  of  forearm ?,?, 

Loin    48 

That  the  sense  of  touch  is  located  in  spots — touch  spots — can  best  be 
demonstrated  on  the  calf  of  the  leg.  If  this  is  shaved  and  then  carefully 
explored  with  a  fairly  stiff  hair,  it  will  be  found  that  there  are  only 
some  twelve  to  fifteen  spots  in  an  area  of  a  square  centimeter  at  which 
the  hair  can  be  felt.  Between  these  spots  there  is  no  sensation  of  touch. 
That  these  spots  are  composed  of  specialized  receptors  can  be  very  clearly 
shown  by  pressing  a  fine  needle  into  one  of  them,  when  no  pain  will  be 
experienced  but  only  a  peculiar  shotty  sense  of  pressure. 

Careful  examination  of  the  position  of  the  touch  spots  will  further 
show  that  they  are  grouped  around  hair  follicles,  particularly  on  the  side 
from  which  the  hair  extends — the  windward  side,  we  may  call  it.  This 
fact  explains  the  well-known  experience  that  an  object  may  be  felt  more 
acutely  on  a  hairy  surface  than  after  that  surface  has  been  shaved.  The 
hairs  bend  slightly  when  the  object  comes  in  contact  with  them,  thus 


794  THE    CENTRAL   NERVOUS    SYSTEM 

causing  pressure  to  be  exerted  on  the  hair  follicles,  so  that  the  touch 
corpuscles  in  the  neighborhood  of  the  follicles,  or  perhaps  the  fine  nerve 
plexus  which  surrounds  them,  becomes  excited.  The  influence  of  hairs 
in  increasing  the  touch  sensation  can  be  demonstrated  by  the  von  Frey 
method;  for  example,  in  one  experiment  over  an  area  of  9  square  mil- 
limeters of  skin  with  hairs  present,  2  milligrams  were  found  to  produce  the 
sensation,  whereas  after  the  hairs  had  been  removed,  it  required  36  milli- 
grams. 

The  frequency  of  touch  corpuscles  differs  very  much  in  different  parts 
of  the  body.  They  are  most  plentiful  on  the  fingers,  relatively  infrequent 
over  the  skin  of  the  back,  and  very  scarce  in  the  skin  directly  over  bpny 
surfaces.  They  are  entirely  absent  from  the  cornea,  the  conjunctiva 
of  the  upper  lid,  and  the  glans  penis.  The  adequate  stimulus  for  touch 
is  evidently  deformation  of  the  surface.  Pressure  exerted  over  all  the 
touch  corpuscles  of  a  portion  of  skin  is  not  felt.  This  can  be  demon- 
strated by  dipping  the  finger  into  mercury.  The  pressure  of  the  mercury 
is  felt  on  the  surface  but  not  in  the  submerged  portion  of  the  finger. 
Touch  is  the  most  responsive  of  all  the  sensations.  Thus,  as  has  already 
been  noted,  a  tuning  fork  can  be  felt  vibrating  by  the  finger  when  to 
the  ear  its  note  is  a  continuous  one,  and  the  stimuli  produced  by  a  re- 
volving serrated  wheel  can  be  felt  by  the  fingers  as  separate  even  up 
to  a  rate  of  five  or  six  hundred  stimuli  per  second.  Adaptation  is  also 
a  marked  feature  of  the  touch  sense,  as  is  the  experience  of  every  one 
who  has  worn  flannel  underclothing  or  a  plate  of  false  teeth. 

Closely  related  to  the  tactile  sense  is  the  power  of  discrimination  be- 
tween two  points.  This  is  tested  by  finding  at  what  distance  the  two 
points  of  a  pair  of  calipers  stand  in  order  to  be  distinguished  as  separate. 
The  result  in  any  given  part  of  the  body  varies  a  little  according  to 
whether  the  points  rest  on  touch  corpuscles  and  according  to  the  rela- 
tionship of  the  calipers  to  the  hair  follicles.  On  an  average,  however, 
we  may  take  the  following  distances  in  millimeters  as  being  those  at 
which  the  two  points  can  be  distinguished  over  different  areas  of  the 
body: 

mm. 

Tip  of  tongue 1.1 

Volar  surface  of  finger  tip 2.3 

Dorsal  of  first  phalanx 6.8 

Palm  of  hand 11.3 

Back  of  hand 31.6 

Back  of  neck 64.0 

Middle  of  back,  upper  arm  and  side 67.1 

It  is  clear  from  this  list  that  the  power  of  discrimination  tends  to 
diminish  in  proportion  to  the  lessening  mobility  of  the  part.    It  is  greatest 


THE  PROPERTIES  OF  EACH  TART  OP  THE  REFLEX  ARC         795 

at  the  tip  of  the  tongue  and  the  tip  of  the  fingers;  it  is  least  on  the 
relatively  immobile  skin  of  the  back.  These  distances  are  much  less  when 
the  points  rest  on  two  touch  corpuscles.  Under  these  conditions,  for  in- 
stance, the  distance  for  the  volar  side  of  the  finger  tip  or  even  for  the 
palm  of  the  hand  may  be  only  one-tenth  of  a  millimeter;  and  for  the 
arm  and  back  it  may  become  reduced  to  half  a  millimeter. 

Localization  of  touch  is  a  very  accurate  process^  at  least  in  the  most 
sensitive  parts  of  the  skin,  but  nevertheless  it  is  very  probably  a  mat- 
ter of  education.  An  evidence  of  this  is  the  fact  that  in  the  much  more 
highly  specialized  retina  the  power  of  localization  of  objects  in  the  visual 
field  is  a  process  of  education  and  experience.  For  this  reason  a  person 
from  whom  a  congenital  cataract  has  been  removed,  can  not  locate  the 
objects  which  he  sees  until  after  he  has  learned  by  his  experience  of  touch, 
taste,  etc.,  to  associate  the  portion  of  the  retina  stimulated  with  a  certain 
part  of  the  visual  field.  If  this  is  true  for  the  retina,  it  is  also  probably 
true  for  touch.  The  famous  experiment  of  Aristotle  is  explicable  on  the 
same  basis.  If  the  fingers  are  crossed  and  a  marble  placed  between  the 
crossed  fingers,  it  will  be  felt  as  double,  since  now  it  touches  two  skin 
surfaces  which  have  not  been  accustomed  to  touch  the  same  object,  but 
educated  to  feel  different  objects.  Experience  associates  those  two  skin 
areas  with  different  objects,  not  with  the  same  object. 

The  Pain  Sense. — It  was  at  one  time  thought  that  the  sensation  of  pain 
was  due  to  overstimulation  of  any  kind  of  receptor,  but  it  is  now  known  that 
for  this,  as  for  other  skin  sensations,  there  exist  special  receptors.  Thus, 
it  is  found  that  in  certain  parts  of  the  body,  such  as  the  cornea,  and  to  a 
certain  extent  in  the  glans  penis,  pain  receptors  alone  are  present,  and 
in  disease  the  sense  of  pain  may  be  entirely  abolished,  whereas  that  of 
touch  remains,  this  condition  being  called  analgesia.  Overstimulation  of 
a  touch  spot  does  not,  as  we  have  seen,  cause  pain  but  only  a  sense  of 
pressure.  Although  pain  is  appreciated  by  special  receptors,  the  charac- 
ter of  the  pain  is  dependent  on  the  other  sense  receptors  simultaneously 
excited;  for  example,  a  throbbing  pain  is  due  to  the  simultaneous  pres- 
sure produced  by  dilated  blood  vessels,  etc.  A  sensation  of  pain  accom- 
panies certain  reflexes  of  a  protective  nature  (nociceptive  reflexes,  page 
825),  and  when  the  reflex  is  absent  the  part  is  likedy  to  suffer  damage.  On 
this  account  the  pain  nerves  may  be  regarded  as  trophic  nerves.  The 
sense  of  pain  may  also  occur  in  structures  which  are  devoid  of  ordinary 
sensibility,  such  as  the  intestine  and  the  ureter. 


CHAPTER  LXXXVIII 

THE  PROPERTIES  OF  EACH  PART  OF  THE  REFLEX 

ARC  (Cont'd) 

THE  NERVE  NETWORK 

In  all  animals  above  the  Celenterates,  no  direct  protoplasmic  continuity 
exists  between  the  various  neurons,  the  transmission  of  the  nerve  impulse 
depending  on  contiguity  rather  than  continuity  of  the  elements  that  con- 
stitute the  reflex  arc.  This  transmission  may  be  effected  through  a  syn- 
apsis coming  in  contact  either  with  dendrites  or  with  nerve  cells.  It  is 
extremely  difficult  to  know  whether  there  is  really  any  anatomic  con- 
tinuity between  the  various  fibers  which  form  the  network  in  the  gray 
matter  of  the  central  nervous  system.  "VVe  shall  not  attempt  to  discuss 
this  vexed  question  here,  but  in  order  that  we  may  learn  something  of  the 
possible  functions  of  a  nerve  network,  we  may  consider  that  present  in 
the  walls  of  the  intestine  (plexus  of  Auerbach  and  Meissner.)  This  plexus 
seems  to  have  an  important  function  to  perform  in  connection  with  the 
myenteric  reflex  (see  page  466).  At  least  it  has  been  shown  by  Meek3  that 
after  transsection  of  the  intestine  the  muscular  and  epithelial  structures  be- 
come regenerated  considerably  earlier  than  the  nervous  plexus,  but  that 
the  myenteric  reflex,  which,  it  will  be  remembered,  is  characterized  by  a 
wave  of  inhibition  preceding  one  of  contraction  does  not  occur  until  after 
the  plexus  has  been  regenerated. 

NETWORK  ON  SKIN  NERVES 

A  very  important  type  of  nerve  network,  from  the  medical  viewpoint, 
is  that  which  is  produced  close  to  their  receptor  endings  by  the  branch- 
ing of  the  afferent  fibers  of  the  skin.  Through  these  branches  the  vas- 
cular reactions  following  the  application  of  an  irritant  to  the  sensory 
surface  take  place  without  the  intervention  of  any  nerve  cells.  It  used 
to  be  thought  that  such  reflex  vasodilatation  depended  upon  the  trans- 
mission of  an  impulse  along  an  afferent  neuron  to  an  efferent  vaso- 
dilator neuron,  a  view  strictly  in  consonance  with  the  neuron  hypothesis. 
That  such  is  not  the  case,  however,  is  shown  by  the  fact  observed  by 
Ninian  Bruce4  that  irritants  such  as  mustard  oil  applied  to  the  skin 
or  cornea  continue  to  produce  their  usual  reaction  for  some  time  after 

796 


THE    PROPERTIES   OF    E3AOH    PART   OK    THE    REFLEX    AUr 


797 


section  of  the  posterior  roots  of  the  spinal  cord,  but  fail  to  do  so  if 
the  nerve  libers  are  cut  and  allowed  1<>  degenerate,  or  if  the  stimuli  are 
blocked  by  applying  cocaine  to  the  skin.  What  actually  happens  is 
evidently  that  the  impulse  set  up  by  the  irritant  as  it  travels  up  the 
.•liferent  fiber  passes  on  to  one  of  the  branches  above  referred  to,  along 
which  it  then  proceeds  to  the  blood  vessels,  which  it  causes  to  dilate. 
That  such  vasodilator  impulses  may  be  transmitted  down  the  fibers  of 
an  afferent  nerve  has  been  confirmed  by  Bayliss,  who  found  that  vaso- 
dilatation occurred  in  the  hind  limb  when  the  posterior  spinal  roots 
were  stimulated  (see  page  234). 

Post,  root 
gang.- 


Fig.  206. — Diagram  to  show  axon  reflex  of  sensory  nerve  fiber  of  skin.  A  stimulus  applied  to 
the  skin  is  transmitted  by  the  sensory  fiber  (.¥),*  part  of  it  going  to  the  spinal  cord  (SC),  and 
part   of   it  passing  by   the   collateral    (C)    to   the   arteriole    {A),   which    it    causes   to    dilate. 

In  this  peripheral  branching  of  the  afferent  fibers  of  the  skin,  we 
have  therefore  a  sort  of  neuropile  which,  like  that  of  certain  forms  of 
Celenterates  (see  page  782),  is  capable  of  serving  as  a  pathway  for  the 
transmission  of  a  sensory  impulse  to  an  effector  organ  without  the  in- 
tervention of  nerve  cells.  Such  a  reflex  is  known  as  an  axon  reflex,  and 
it  is  evident  that  it  may  occur  through  any  fiber  which  gives  off  branches, 
one  traveling  to  a  sensory  surface,  the  other  to  some  effector  organ,  as 
occurs  in  the  hypogastric  nerves  to  the  bladder  (see  page  883). 


THE  SYNAPSIS 

At  the  point  of  contact  between  a  branch  of  one  neuron  and  a  nerve 
cell  of  the  next,  we  have  seen  that  there  exists  a  structure  known  as 
the  synapsis.     Although  this  is  described  by  histologists  as  a  tuft-like 


798 


THE    CENTRAL    NERVOUS   SYSTEM 


branching  of  the  end  of  the  axon  (Fig.  207),  it  may  really  consist  of  a 
sort  of  membrane — the  synaptic  membrane.  It  permits  the  nerve  im- 
pulse to  pass  in  one  direction  only,  from  synapsis  to  cell.  Of  what  this 
membrane  may  be  composed,  we  do  not  know,  but  there  can  be  no 
doubt  as  to  its  great  functional  importance  in  connection  with  the  in- 
tegration of  the  central  nervous  system;  for  example,  failure  of  an  im- 
pulse to  pass  between  two  neurons  may  be  due  to  retraction  of  the 
synaptic  membrane  from  the  cell,  or  to  alteration  in  its  permeability  to- 
wards the  nerve  impulse,  perhaps  as  a  consequence  of  changes  in  surface 


Fig.  207. — Arborization  of  collaterals  from  the  posterior  root  fibers  around  the  cells  of  the 
posterior  horn.  A,  ascending  fiber  in  posterior  columns;  B,  collaterals;  C,  cells  of  posterior  horn; 
E,    synapsis.      (From    Ramon    y    Cajal.) 


tension.  Similar  changes  may  also  be  brought  about  by  the  action  of 
electrolytes  or  by  chloroform,  strychnine,  and  other  drugs.  As  we  shall 
see  when  Ave  come  to  study  the  reflexes  of  the  higher  animals,  there  can 
be  little  doubt  that  it  is  in  the  synaptic  membrane  that  many  of  the 
peculiarities  reside  which  characterize  conduction  in  a  reflex  arc  as 
compared  with  that  in  a  nerve  trunk.  The  phenomena  of  summation, 
of  reciprocal  inhibition,  of  facilitation,  etc.,  are  undoubtedly  depend- 
ent upon  such  alterations.  The  synapsis  is  also  almost  certainly  the 
seat  of  fatigue  in  the  central  nervous  system,  and  it  is  possibly  the 
structure  whose  physiologic  activity  becomes  upset  in  surgical  shock. 


THE  PROPERTIES  OF  EACH  PART  OF  THE  REFLEX  ARC 


790 


THE  NERVE  CELL 

Aside  from  being  a  meeting  place  of  fibers  coming  from  various 
sources,  the  nerve  cell  may  have  other  functions,  such  as  that  of  rein- 
forcing impulses,  just  as  a  relay  may  reinforce  an  elect  fie  current.  It 
is  also  responsible  for  maintaining  the  nutrition  of  the  axon  with  which 
it  is  connected.     In  the  case  of  the  posterior  root  fibers  of  higher  ani- 


J/:  v^  '  ■  -SJ- v*^ 


Fig.    208. — Normal    cell    from    the    anterior    horn,    stained    to    show    Nissl's    granules.      a,    the    axon. 

(From    Howell.) 


mals,  this  function  is  probably  the  most  important  which  the  cell  per- 
forms, for  it  has  been  found  by  separating  the  ganglia  from  their  blood 
supply  in  the  frog  that,  although  the  cells  degenerate  in  about  two 
weeks,  sensory  impulses  continue  to  be  transmitted  through  the  gan- 
glia. Similar  observations  have  been  made  in  the  case  of  the  crab,  in 
which  the  cell  bodies  of  the  neurons  lie  on  the  surface  of  the  ganglion 


800 


THE    CENTRAL    NERVOUS   SYSTEM 


mass,  from  which  they  can  be  separated,  leaving  merely  the  neuropile, 
through  which,  however,  the  reflex  continues  to  be  conveyed.  After  a 
time,  of  course  in  this  case  also  the  reflex  disappears,  because 
an  axon  can  not  live  indefinitely  after  it  has  been  separated  from  its 
nerve  cell. 

These  facts  regarding  the  general  function  of  the  nerve  cell  arouse 
our  curiosity  as  to  its  morphologic  structure.  When  nerve  cells  are 
fixed  and  stained  in  various  ways  they  show  certain  elements  in  the 


Fig.  209. — Part  of  an  anterior  cornual  cell  from  the  calf's  spinal  cord,  stained  to  show  neurofibrils: 
ax,  axon;   a,   b,   c,   dendrites.      (From   Bethe.) 

cytoplasm — namely,  (1)  large  granules  or  masses,  which  stain  deeply 
with  basic  dyes  and  are  called  Nissl  bodies  (Fig.  208),  and  (2)  a  fine 
network  of  fibrils  passing  through  the  cell  substance  from  one  process  or 
dendrite  to  another — neurofibrils  (Fig.  209).  These  appearances  in  fixed 
and  stained  preparations  are  possibly,  however,  entirely  artificial ;  for  when 
nerve  cells  are  preserved  in  a  living  state — by  being  suspended  in  some  of 
the  animal's  own  lymph  or  blood  serum — it  is  found,  when  they  are  ex- 
amined by  the  aid  of  the  ultramicroseppe  (seo  page  52);  that  the  cytoplasm 


Tin:  PROPERTIES  OF  BACH  PART  OF  THE  REFLEX  ARC        801 

is  composed  of  a  viscous  fluid  full  of  extremely  minute  granules,  each  of 
which  apparently  consists  of  a  colloidal  solution  surrounded  by  a  lipoid 
envelope  (Fig.  210).  When  the  temperature  is  raised,  the  granules  dis- 
appear, and  when  the  cells  are  deprived  of  oxygen,  the  cytoplasm  and 
nucleus  become  swollen.  A  similar  swelling  of  the  cell  and  nucleus  super- 
venes upon  section  of  the  axon;  and  in  stained  specimens  the  Nissl 
granules  disappear  and  the  protoplasm  stains  diffusely  (chromatolysis). 
In  embryonic  life  the  processes  of  the  nerve  cells  appear  to  be  capa- 
ble of  undergoing  a  certain  amount  of  ameboid  movement,  and  fibers 
grow  out  from  them,  indicating,  therefore,  that  in  the  development 
of  the  nervous  system  the  nerve  cells  appear  first,  and  the  nerves  sub- 
sequently grow  out  from  them  to  their  proper  destination.  Prolifera- 
tion of  isolated  tissue  cells  in  vitro  has  been  observed  for  many  other 


Fig.  210. — Living  nerve  cells  (from  the  dorsal  root  ganglia  of  a  dog  three  days  old)  examined 
by  the  ultramicroscope.  There  are  no  Nissl  bodies  or  neurofibrils,  only  fine  particles,  present  in 
the   protoplasm.      (From   Marinesco.) 

tissues,  such  as  cardiac  muscle,  renal  epithelium  and  connective  tis- 
sue. Its  occurrence  indicates  that  the  therapeutic  principle  that  the 
aim  of  treatment  should  be  to  give  the  diseased  organ  a  rest  so  that  by 
cell  regeneration  it  may  recover  its  lost  function,  is  one  which  may  ap- 
ply to  the  nerve  tissues  of  young  animals.  Whether  adult  nerve  cells 
may  regenerate  is  as  yet  not  certain. 

This  growing  out  of  nerve  fibers  from  their  cells  is  the  essential  na- 
ture of  the  development  of  the  nervous  system  in  the  developing  animal. 
At  birth,  unlike  the  cells  of  other  tissues,  those  of  the  central  nervous 
system  are  already  provided.  No  new  ones  are  added  during  postnatal 
life.  The  axons  gradually  develop  from  this  inherited  stock  of  nerve 
cells,  and  by  connecting  with  other  neurons  serve  to  bring  about  the 
integration  which  is  the  important  characteristic  of  the  adult  nervous 


802  THE    CENTRAL    NERVOUS    SYSTEM 

system.     The  more  complex  the  integration,  the  higher  the  intelligence 
of  the  animal. 

Besides  performing  these  functions  the  nerve  cells  serve  as  store- 
houses for  memory  impressions,  certain  types  of  them  being  especially 
adapted  for  this  function.  The  differences  observed  in  the  relative  thick- 
ness of  the  cell  layers  composing  the  cerebral  cortex  are  more  or  less 
associated  with  the  function  which  it  can  be  shown  the  different  areas 
of  this  possess.  Nerve  cells  are  extraordinarily  sensitive  to  deficiency 
in  oxygen  supply,  and  yet  little  evidence  of  oxygen  consumption  by 
the  brain  can  be  revealed  by  the  usual  methods  of  investigation  (page 
39-6). 

THE  INTERMEDIATE  OR  INTERNUNCIAL  NEURON 

It  would  be  profitless  at  this  stage  to  consider  the  possible  influences 
that  the  intermediate  neuron  may  have  on  the  impulses  passing  along 
the  reflex  arc.  Before  doing  so  we  must  see  how  the  problem  can  be 
approached,  for  it  is  plain  that  the  neuron  in  the  case  of  the  simpler 
reflexes  is  too  short  to  make  any  investigation  of  its  peculiar  functions 
a  possibility.  We  must  study  the  characteristics  of  some  type  of  re- 
flex in  which  this  neuron  is  drawn  out,  such  as  the  scratch  reflex,  in 
which,  as  we  shall  see,  it  extends  from  the  shoulder  area  of  the  cord 
to  the  lumbar  region. 


CHAPTEK  LXXXIX 

THE  REFLEXES  OF  THE  SPINAL  ANIMAL  AND 
SPINAL  SHOCK 

Having  become  familiar  with  the  peculiar  properties  of  each  of  the 
structures  which  go  to  make  up  the  reflex  arc,  we  may  now  proceed  to 
consider  the  function  of  the  arc  as  a  whole.  It  may  he  well  first  of  all 
to  consider  briefly  the  experimental  method  by  which  such  studies  may 
be  made.  The  object  aimed  at  is  to  simplify  the  conditions  as 
much  as  possible,  for  it  will  be  evident  that,  in  the  intact  nervous  sys- 
tem, with  the  brain  exercising  a  dominating  influence  over  the  great 
majority  of  all  the  reflexes,  it  would  be  impossible  by  applying  a  given 
stimulus,  to  predict  exactly  what  kind  of  reflex  response  it  might  call 
forth.  The  reflex  will  be  conditioned  upon  the  accompanying  influence 
which  the  brain  exercises  on  the  reflex  involved. 

In  order  to  render  the  reflex  unconditioned,  Ave  must  remove  the  in- 
fluence of  higher  centers.  This  can  be  done  experimentally  for  the  re- 
flexes of  a  great  part  of  the  body  by  cutting  the  spinal  cord  above  the 
level  of  the  segment  in  which  the  reflex  under  investigation  resides. 
Some  of  the  reflexes  elicitable  from  the  cord  isolated  in  this  way  in- 
volve .  only  one  or  two  neighboring  segments,  whereas  others  spread 
over  several.  The  reflexes  which  have  been  most  extensively  employed 
are  those  which  involve  the  musculature  of  the  hind  limbs.  Since  some 
of  the  receptors  concerned  come  from  the  skin  of  the  flank  and  shoul- 
der areas,  the  section  is  usually  made  at  the  upper  end  of  the  thoracic 
region  of  the  spinal  cord. 

Spinal  Shock  in  Laboratory  Animals 

Immediately  after  the  operation  a  profound  condition  of  depression  sets 
in,  involving  all  the  reflex  arcs  in  the  separated  portion  of  cord.  This 
condition  is  known  as  spinal  shock.  It  supervenes  in  all  classes  of  ani- 
mals having  a  spinal  cord,  but  is  much  more  profound  in  the  higher 
than  in  the  lower  animals.  As  a  result  of  this  depression,  the  part  of 
the  body  below  the  section  exists  in  a  limp  and  flaccid  condition,  and  the 
application  of  even  very  strong  stimuli  to  the  skin  will  evoke  no  form 
of  reflex  movement.    In  the  case  of  the  lower  animals,  such  as  the  frog, 

803 


804  THE    CENTRAL   NERVOUS    SYSTEM 

the  condition  begins  to  pass  off  in  from  twenty  minutes  to  half  an  hour, 
after  which  a  stimulus  applied  to  the  skin  of  the  foot  is  followed  by  a 
typical  flexion  movement  at  knee  and  hip,  the  so-called  flexion  reflex. 
In  the  rabbit  very  little  reflex  response  is  elicitable  for  several  hours 
after  the  operation,  but  in  a  few  days  the  reflexes  return  completely 
below  the  level  of  the  section.  In  the  dog,  on  which  a  great  deal  of 
work  has  been  done,  the  involved  regions  of  the  body  are  profoundly 
paralyzed.  The  skin  is  in  a  more  or  less  unhealthy,  unnatural  condi- 
tion, the  surface  cold,  the  hairs  ruffled;  and  if  care  is  not  taken,  the 
slightest  abrasion  of  the  surface  may  result  in  a  nasty  ulceration.  On 
account  of  the  paralysis  of  the  centers  of  micturition  and  defecation, 
there  is  also  incontinence  of  urine  and  of  feces. 

The  Reflexes  in  the  Spinal  Animal 

With  reasonable  attention,  however,  the  dog  makes  a  wonderful  re- 
covery. After  an  interval  of  two  weeks  the  hind  limbs,  although  com- 
pletely paralyzed  so  far  as  voluntary  movement  is  concerned,  begin  to 
show  considerable  signs  of  improvement.  The  first  reflexes  to  return 
are  those  concerned  with  the  deeper  structures,  such  as  the  vascular 
reflexes,  thus  bringing  the  skin  back  to  its  normal  temperature  and 
condition.  The  reflexes  of  micturition  and  defecation  also  soon  return, 
so  that  the  animal  no  longer  suffers  from  the  continuous  discharge  of 
urine  and  feces.  About  the  same  time  the  knee-jerk  becomes  elicitable. 
This  reflex  is  obtained  by  tapping  the  tendon  which  connects  the  patella 
with  the  tibia,  the  response  being  a  smart  contraction  of  the  extensor 
muscles  of  the  knee  joint.  The  flexion  reflex  also  begins  to  reappear. 
This  is  elicited  by  applying  a  pinprick  or  other  hurtful  stimulus  to 
the  skin  of  a  lower  extremity,  and  when  fully  developed  consists  in  a 
flexion  of  the  knee  and  hip  joints.  The  evident  object  of  this  move- 
ment is  that  the  stimulated  parts  may  be  removed  from  the  source  of 
stimulation,  and  it  is  plain  that  all  stimuli  that  produce  the  flexion 
reflex  are  such  as  would  cause  in  the  intact  animal  a  sensation  of  pain. 
Such  stimuli  are  thus  classified  as  nocuous,  and  the  reflex  is  styled  a 
nociceptive  reflex.  Accompanying  flexion  of  the  stimulated  limb  the  op- 
posite or  contralateral  limb  usually  undergoes  a  definite  extension, 
called  the  crossed  extension  reflex.  The  occurrence  of  this  together  with 
the  flexion  of  the  stimulated  limb  is  an  important  thing  to  remember 
in  testing  the  reflexes  in  man.  Malingerers  who  attempt  to  make  it  ap- 
pear that  they  have  some  lesion  of  the  spinal  cord  may  know  that  if 
such  lesion  exists  no  movement  of  the  leg  occurs  when  the  skin  is 
stimulated,  but  they  are  unlikely  to  know  that  under  these  conditions 
the  opposite  leg  also  fails  to  show  a  simultaneous  extension. 


REFLEXES   IN    THE   SPINAL    ANIMAL   AND   SPINAL   SHOCK  805 

That  the  nociceptive  reflexes  should  be  among  the  first  to  return  after 
spinal  transection  is  of  considerable  interest  as  indicating  their  im- 
portance in  the  protection  of  the  animal  from  injury.  They  are  the 
essential  reflexes  of  defense,  and  it  is  considerably  later  in  the  recovery 
of  the  animal  before  reflexes  dependent  upon  stimulation  of  other  tac- 
tile receptors  begin  to  show  themselves.  The  most  important  of  this 
latter  group  of  more  special  reflex  movements  include  the  so-called 
scratch  reflex  and  the  extensor  thrust.  The  scratch  reflex,  as  its  name 
implies,  is  the  scratching  movement  of  flexion  and  extension  of  the  hind 
limb  at  a  rate  of  about  four  contractions  per  second  that  occurs  when 
a  mechanical  stimulus  is  applied  to  the  flank  and  shoulder  area  of  the 
animal.  For  example,  if  Ave  gently  draw  a  pencil  or  the  fingers  back- 
ward and  forward  among  the  hairs  on  this  region  of  the  spinal  animal, 
the  corresponding  hind  limb  will  be  brought  up  so  that  the  claws  are 
approximately  at  the  place  stimulated,  and  the  limb  thus  directed  will 
undergo  a  series  of  flexions  and  extensions,  designed  evidently  for  the 
purpose  of  scratching  the  area  of  skin  that  has  been  stimulated.  If  the 
stimulus  is  a  weak  one,  only  the  initial  stages  of  the  movement  may 
occur,  such  as  the  preliminary  flexion  of  the  leg.  As  we  have  already 
stated,  the  receptive  stimulus  calling  forth  this  reflex  is  very  specific 
in  nature.  A  pinprick  or  rough  friction  of  the  reflex  area  will  not  produce 
it,  nor  will  the  application  of  heat  or  of  a  single  electric  shock.  The 
most  adequate  stimulus  is  one  simulating  as  nearly  as  possible  the  con- 
dition which  would  be  produced  by  the  movement  on  the  flank  of  the 
animal  of  some  insect.  This  more  or  less  complicated  scratch  reflex  can 
of  course  also  be  elicited  in  animals  whose  spinal  cord  has  not  been  cut, 
but  we  can  not  predict  in  such  cases  whether  the  reflex  will  occur.  The 
brain  may  inhibit  the  reflex  arc  and  prevent  the  movement.  In  a  spinal 
animal,  however,  the  reflex  always  occurs  provided  an  adequate  stimulus 
is  applied.  The  great  importance  of  the  scratch  reflex  in  the  study  of 
the  physiology  of  the  spinal  cord  rests  in  the  fact  that  a  large  stretch 
of  cord  is  involved  in  the  reflex  path.  The  afferent  impulses  must  enter 
at  a  much  higher  level  than  the  efferent  impulses  leave,  and  between 
these  two  points  there  must  exist  a  long  intraspinal  neuron  (see  page 
813).  This  permits  us  to  study  many  conditions  influencing  reflex  action 
which  otherwise  in  a  reflex  located  in  one  segment  only  it  would  be  im- 
possible to  investigate. 4a 

The  extensor  thrust  is  elicited  by  applying  pressure  to  the  pad  of  the 
paw  or  the  sole  of  the  foot.  It  consists  of  a  quick  extension  movement 
of  the  corresponding  limb  usually  with  a  flexion  of  the  opposite  limb. 

After  complete  recovery  from  shock,  the  paralyzed  parts  of  the  body 
are  capable  of  performing  even  more  complex  movements  than  those  al- 


806  THE    CENTRAL   NERVOUS    SYSTEM 

ready  mentioned.  For  example,  if  the  animal  is  held  up  with  the  hind 
legs  hanging  down,  these  "will  often  exhibit  rhythmic  flexion  and  exten- 
sion movements,  with  the  two  limbs  acting  alternately,  as  they  would 
in  walking  or  running.  This  is  sometimes  called  the  mark-time  reflex. 
Another  complicated  movement  may  be  produced  by  placing  the  animal 
in  water,  when  it  may  make  the  movements  of  swimming,  but  its  swim- 
ming will  not  be  sufficient  to  keep  it  on  the  surface.  These  swimminsr 
movements  are  more  perfect  in  the  spinal  frog. 

After  complete  recovery  from  spinal  shock,  the  hind  limbs  are  more 
or  less  in  a  condition  of  extension  contracture :  the  vascular  and  other 
visceral  reflexes  are  in  perfect  condition,  and  a  marked  rise  in  blood 
pressure  occurs  when  one  of  the  sensory  nerves  of  the  hind  limb  is 
stimulated — an  experiment  which  can  be  performed  in  such  animals 
without  the  administration  of  any  anesthetic,  since  the  animal  feels 
no  pain.  In  female  spinal  animals  impregnation  may  occur  and  preg- 
nancy proceed  in  normal  fashion  accompanied  by  the  usual  secretion 
of  milk.     The  significance  of  this  fact  will  be  dwelt  upon  later. 

SPINAL  SHOCK  IN  MAN 

As  Ave  ascend  the  animal  scale  we  find  that  recovery  from  spinal  shock 
takes  longer  and  longer  to  occur  and  becomes  less  and  less  perfect.  In 
the  case  of  man,  recovery  is  never  complete,  for  a  permanent  condition, 
which  has  been  called  "isolation  dystrophy,"  supervenes  before  the 
symptoms  of  shock  have  been  recovered  from.  The  tendon  jerks  are 
permanently  abolished  in  complete  lesions  of  the  cord  in  man,  and  even 
when  the  lesion  involves  only  one  lateral  half  of  the  cord,  this  reflex 
is  either  entirely  absent  or  very  feeble  on  the  corresponding  side,  though 
normal  on  the  other  (Holmes5).  Severe  lesions  above  the  lower  dorsal 
region  practically  always  leave  the  legs  in  a  permanently  flaccid  con- 
dition, with  accompanying  atrophy,  but  sometimes  automatic  movements 
of  flexion  and  extension,  like  those  of  the  mark-time  reflex,  may  set  in. 

When  the  injury  of  the  cord  is  less  severe,  the  limb  musculature  is 
flaccid  and  toneless  for  some  time,  the  tendon  jerk  and  the  abdominal 
and  cremasteric  skin  reflexes  being  entirely  absent.  After  some  time, 
however — it  may  be  as  early  as  ten  days — the  muscles  begin  to  reac- 
quire some  tone,  and  a  little  later  the  tendon  jerk  becomes  elicitable. 
Regarding  the  behavior  of  the  flexion  reflex  after  spinal  injuries  in 
man,  it  has  been  found  that  the  part  of  it  known  as  the  Bakinski  reflex 
is  not  elicitable  after  severe  lesions,  but  in  those  that  are  less  severe 
a  flexion  of  the  great  toe  may  occur  on  stimulation  of  the  sole.  Later 
this  movement  may  be  accompanied  by  contraction  of  the  hamstrings, 
and  later  still,  in  favorable  cases,  by  flexion  at  knee  and  hip.     In  these 


REFLEXES    l\    THE    SPINAL    ANIMAL   AND   SPINAL   SHOCE  807 

cases  also  the  Babinski  reflex  changes  from  a  flexion  to  an  extension 
of  the  great  toe.  It  is  important  to  note  in  connection  with  the  above 
association  of  movements,  thai  the  sensory  area  of  the  sole  is  connected 
with  the  same  segment  of  the  spinal  cord  that  furnishes  the  motor 
fibers  to  the  flexors  of  the  toes  and  the  hamstrings  (first  sacral.)  The 
recovery  after  shock  therefore  sets  in  earlier  for  unisegmental  reflex 
areas  than  for  those  involving  several  segments. 

The  Cause  of  Spinal  Shock 

The  relationship  of  the  profundity  of  spinal  shock  to  the  phylogenetic 
position  of  the  animal  indicates  that  the  shock  must  be  due  to  the 
isolation  of  the  lover  spinal  segments  from  the  hicrher  centers  (Pike6). 
Tt  has  been  suggested  that  the  spinal  section  in  the  higher  but  not  in 
the  lover  animals  breaks  a  nervous  patlway  in  which  normally  the 
reflex  impulses  travel.  According  to  this  view,  the  afferent  impulse, 
when  it  enters  the  spinal  cord  in  the  lower  animals,  chooses  the  shortest 
possible  route  to  the  effector  neuron  of  the  same  or  closely  adjacent  seg- 
ments bv  the  collateral  branches  springing  from  the  sensory  neuron. 
In  the  higher  animals,  however,  it  would  appear  that,  although  this  local 
spinal  pathway  is  present  and  may  be  taken,  yet  it  is  usually  passed 
bv  and  the  impulse  travels  up  to  the  higher  centers,  from  which  it  is 
then  transmitted  bv  the  pyramidal  tracts  to  the  motor  neurons  con- 
cerned. This  would  appear  to  be  the  pathway  for  nervous  reflex  im- 
pulses in  higher  animals — the  beaten  track.  "When  the  spinal  cord  is 
severed,  therefore,  the  condition  of  shock  supervenes  because  impulses 
have  not  yet  learned  that  they  may  find  a  shorter  road  to  the  motor 
neuron  by  the  collateral  than  by  the  pathway  which  they  usually  travel. 
Thev  learn  this  only  after  some  time,  which  explains  the  slow  re- 
covery of  the  reflexes  from  shock. 

It  is  obviously  a  difficult  matter  to  supply  direct  proof  in  support  of 
the  above  hypothesis  of  the  cause  of  spinal  shock,  but  besides  the  in- 
direct evidence  furnished  by  observations  on  the  degree  to  which  this 
condition  supervenes  in  different  groups  of  anmials,  the  hypothesis 
also  conforms  well  with  all  the  other  facts  which  we  know  regarding 
the  condition.  For  example,  it  is  well  known  that  the  portion  of  the 
body  above  the  transection  of  the  spinal  cord  in  no  way  suffers  from 
the  shock.  Sherrington  has  described  a  monkey  the  cord  of  which  was 
cut  below  the  cervical  region,  and  which  immediately  after  the  opera- 
tion amused  itself  by  catching  flies  with  the  anterior  extremities,  whereas 
the  posterior  extremities  were  in  a  condition  of  the  profoundest  shock. 
Such  experiments  farther  indicate  that  the  shock  can  not  be  dependent 


808  THE    CENTRAL   NERVOUS   SYSTEM 

upon  the  lowering  of  arterial  blood  pressure  which  a  section  of  the 
cord  higher  than  the  mid-dorsal  region  must  entail.  The  poor  nutritive 
condition  of  the  skin  which  we  have  seen  to  exist  in  the  hind  limbs 
in  shock,  shows  that  the  blood  vessels  in  them  are  profoundly  dilated, 
but  evidently  the  fall  in  blood  pressure  has  nothing  to  do  with  the 
faulty  conduction  through  the  spinal  cord,  for  such  a  fall  would  affect 
the  centers  for  the  fore  limbs  as  well  as  those  for  the  hind,  and  yet 
the  former  show  no  symptoms  of  shock. 

Exactly  similar  shock  is  obtained  by  any  section  of  the  spinal  cord 
as  high  up  as  the  medulla.  Of  course  as  the  section  is  made  higher  and 
higher  up,  the  resulting  paralysis  becomes  more  and  more  marked,  and 
may  reach  such  a  degree  of  severity  that  recovery  of  the  animal  be- 
comes an  impossiblity. 

When  we  come  to  consider  the  functions  of  the  various  parts  of  the 
brain,  we  shall  have  occasion  to  study  the  effects  following  section  at 
higher  levels  of  the  cerebrospinal  axis.  Meanwhile,  however,  it  is  im- 
portant to  note  that  when  a  section  is  made  across  the  crura  cerebri,  so 
that  the  cerebral  hemispheres  alone  are  isolated  from  the  rest  of  the 
nervous  system,  a  condition  of  contracture  of  all  of  the  extensor  muscles 
occurs.    This  condition  is  known  as  decerebrate  rigidity. 


CHAPTER  XC 
PHYSIOLOGICAL  PROPERTIES  OF  THE  SIMPLE  REFLEX  ARC 

We  may  now  proceed  to  study  the  properties  of  reflex  action  occur- 
ring through  the  isolated  spinal  centers  of  a  spinal  animal.  There  are 
two  aspects  of  the  question  to  be  considered:  (1)  the  properties  of  a 
single  reflex  arc,  and  (2)  the  action  or  influence  of  one  reflex  arc  on 
another.  The  importance  of  the  latter  will  be  evident  when  it  is  re- 
membered that  complicated  muscular  movements  depend  for  their  proper 
coordination  entirely  on  the  interaction  between  the  various  reflex  arcs 
which  compose  the  nervous  system.  This  interaction,  as  already  ex- 
plained, has  been  called  by  Sherrington  the  integration  of  the  nervous 
system. 

Probably  the  simplest  way  to  study  the  physiologic  properties  of 
the  simple  reflex  is  to  compare  the  mode  of  conduction  of  a 
nerve  impulse  through  it  with  conduction  along  a  simple  nerve  trunk. 
By  comparing  the  two  .modes  of  conduction  we  shall  be  better  able  to 
appreciate  the  modifications  to  which  the  impulse  is  subjected  by  con- 
duction through  the  reflex  arc.     The  important  points  are  these: 

1.  The  Latent  Period. — The  latent  period,  or  period  which  intervenes  be- 
tAveen  the  moment  of  application  of  the  stimulus  and  the  response,  is 
very  short  in  the  case  of  a  nerve  trunk,  and  under  normal  conditions 
always  the  same,  but  is  quite  variable  and  sometimes  very  long  in  the 
case  of  a  reflex  arc.  Thus,  in  the  case  of  the  conjunctival  reflex,  which 
is  produced  by  applying  a  stimulus  to  the  corneal  conjunctiva  (causing 
a  closing  of  the  eyelids),  the  reflex  time  is  very  short  and  invariable, 
whereas  in  the  case  of  the  scratch  reflex  it  may  vary  from  two  and  a 
half  to  three  and  a  half  seconds,  according  to  the  strength  of  the  stimu- 
lus. The  seat  of  delay  in  the  reflex  arc  is  probably  in  the  synapse,  but 
its  cause  is  obscure. 

2.  Grading  of  Intensity. — In  a  nerve  trunk  the  intensity  of  the  im- 
pulse is  more  or  less  proportional  to  the  strength  of  the  stimulus.  This 
can  be  judged  by  observing  either  the  action  current  in  the  nerve  by 
means  of  a  galvanometer  or  the  response  of  the  end  organ;  e.  g.,  muscle, 
attached  to  the  nerve.  In  the  case  of  a  reflex  arc,  on  the  other  hand, 
there  is  by  no  means  so  evident  a  parallelism  between  stimulus  and 
response.  Reflexes,  however,  vary  considerably  in  this  regard.  The 
conjunctival  reflex  and  the  extensor  thrust  behave  according  to  the  so-called 
"all  or  nothing  principle;"  i.e.,  the  intensity  of  the  response  is  more  or 
less  independent  of  the  strength  of  the  stimulus.  In  other  reflexes,  such 
as  the  flexion  reflex  and  the  scratch  reflex,  the  intensity  of  the  response 

809 


810  THE    CENTRAL    NERVOUS    SYSTEM 

is  much  more  nearly  proportional  to  the  strength  of  the  stimulus.  Thus, 
a  feeble  stimulus  applied  to  the  flank  calls  forth  only  a  slight  flexion 
of  the  hind  limb  of  the  same  side,  whereas  a  stronger  stimulus  sets 
going  a  typical  scratching  movement. 

3.  After-effect. — When  a  stimulus  is  removed  from  a  nerve,  the  effect 
which  it  produces,  as  judged,  for  example,  by  the  action  current,  im- 
mediately disappears.  There  is  no  after-response.  In  reflex  arcs,  how- 
ever, such  a  phenomenon  is  usually  well  marked.  Particularly  is  this 
the  ease  in  the  flexion  and  scratch  reflexes  of  the  spinal  dog.  A  mo- 
mentary stimulus  of  optimal  strength  applied  to  the  scratch  skin-area 
may  produce  no  immediate  response,  but  after  its  removal  a  violent 
scratching  movement  may  set  in.  This  after-discharge,  in -cases  in  which 
the  stimulus  is  strong,  may  indeed,  as  in  the  flexion  reflex,  be  more 
marked  than  the  response  during  the  time  of  application  of  the  stimulus. 
In  this  particular  reflex,  the  after-discharge  often  takes  the  form  of  a 
clonus,  with  a  rate  of  contraction  of  from  seven  and  a  half  to  twelve 
per  second.  The  crossed  extension  reflex  also  has  a  very  pronounced 
after-discharge,  which  may  outlast  the  stimulus  for  from  ten  to  fifteen 
seconds.  Regarding  the  phenomenon  of  after-discharge,  Sherrington 
has  stated  that  there  is  "no  feature  of  the  conduction  of  a  reflex  arc 
which  distinguishes  its  mechanism  more  universally  from  that  of  a 
nerve  fiber,  tract  or  trunk  than  lengthy  after-discharge." 

4.  Summation. — "When  a  subliminal  stimulus — that  is,  one  that  has 
in  itself  no  visible  effect — is  frequently  repeated  in  the  case  of  a  nerve, 
no  response  occurs.  In  the  case  of  a  reflex  arc,  however,  such  repeti- 
tion of  subliminal  stimuli  ultimately  calls  forth  response.  This  sum- 
mation is  very  evident  in  the  case  of  the  scratch  reflex ;  e.  g.,  one  or 
two  electrical  stimuli  applied  to  the  scratch  field-area  call  forth,  as  a 
rule,  no  movement  of  the  corresponding  hind  leg,  but  if  these  same 
stimuli  are  frequently  repeated,  the  typical  reflex  scratching  movement 
will  occur.  Evidently,  then,  in  a  reflex  arc  there  is  a  considerable 
amount  of  resistance  towards  a  single  stimulus,  which  resistance  is 
overcome  by  a  succession  of  stimuli.  In  other  words,  the  threshold  of 
the  excitability  of  the  reflex  mechanism  becomes  loAvered  as  a  result 
of  its  previous  stimulation.  Each  stimulus  excites  the  sensory  surfne* 
so  that  it  responds  more  easily  to  the  sneceeding  stimulus. 

5.  Irreversibility  of  the  Direction  of  Conduction. — This  is  well  illus- 
trated in  the  so-called  Bell-Magendie  law  of  conduction  in  the  spinal 
nerve  roots.  A  motor  impulse  travels  out  of  the  cord  by  the  anterior 
roots,  while  a  sensory  impulse  travels  in  by  the  posterior.  This  direc- 
tive influence  can  not  depend  on  the  nerve  trunks  or  the  nerve  cells,  for 
nerve  trunks  conduct  equally  in  both  directions,  and  so  also  must  the 
nerve  cell.     The  irreversibility  must  therefore  depend  on  the  synaptie 


PHYSIOLOGICAL   PROPERTIES   OK    THE   SIMPLE    REFLEX    ARC  811 

connections.  It  can  be  demonstrated  by  observing  the  action  cur- 
rent produced  in  the  spinal  cord  by  stimulating  the  anterior  or  posterior 
spinal  roots.  In  the  former  case  no  action  current  is  observed,  but  it  is 
very  evident  in  the  latter  case. 

6.  The  Refractory  Period.— This  has  been  well  defined  by  Sherrington 
as  being  "a  state  during  which  apart  from  fatigue  the  mechanism  shows 
less  than  its  full  excitability."  We  are  already  familiar  with  the  re- 
fractory period  in  the  cases  of  the  heart  muscle  and  the  musculature  of 
the  esophagus  and  intestine.  For  example,  the  application  of  a  stimu- 
lus to  the  quiescent  frog  heart  while  it  is  contracting  in  response  to  an  im- 
mediately preceding  stimulus  fails  to  produce  any  further  effect.  The  re- 
fractory period  is  extremely  brief  (one  thousandth  of  a  second)  in  a 
nerve  trunk,  but  is  much  longer  in  a  reflex  arc,  being  probably  longest 
in  the  case  of  the  scratch  reflex,  in  which  it  is  demonstrated  by  the 
fact  that,  however  frequently  we  apply  suitable  stimuli  to  the  sensory 
surface,  the  rhythm  of  response  of  the  contracting  limb  is  always  the 
same.  After  each  stimulus,  therefore,  a  refractory  period  must  become 
developed  during  which  a  repetition  of  the  stimulus  has  no  effect.  It 
is  evident  that  the  existence  of  the  refractory  period  is  the  factor 
responsible  for  the  rhythm  of  the  movements. 

It  is  interesting  to  consider  the  exact  structure  of  the  reflex  arc  that 
is  responsible  for  the  existence  of  the  refractory  phase.  It  obviously 
can  not  be  a  function  of  the  motor  neuron,"  for  through  the  same  motor 
neuron  may  be  discharged,  at  one  time,  impulses  which  bring  about  the 
scratching  movement  and,  at  another,  those  causing  a  tonic  flexion  of 
the  same  muscles.  Nor  can  the  seat  of  the  refractory  period  be  in  the 
sensory  area  of  the  skin  or  the  afferent  neuron,  for  if  a  scratch  move- 
ment is  elicited  by  stimulation  at  a  point  A  in  the  proper  skin  area, 
the  rhythm  of  response  .  which  it  calls  forth  will  not  in  any 
way  be  altered  by  the  application  of  a  second  stimulus  applied  at  7? 
at  some  distance  from  A  and  having  a  different  frequency  (Fig.  211). 
There  is  evidently,  therefore,  some  part  of  the  reflex  arc  that  is  common  to 
impulses  starting  both  at  A  and  at  7>,  for  if  in  each  of  these  spots  a  refrac- 
tory phase  occurred,  then  there  would  be  interference  before  the  two  im- 
pulses had  reached  the  centers  of  the  spinal  cord.  By  exclusion,  there- 
fore, "the  seat  of  the  refractory  phase  seems  to  lie  somewhere  central 
to  the  receptive  neuron  in  the  afferent  arc"— (Sherrington18). 

Many  other  types  of  reflex  activity  illustrate  rhythm  due  to  the  re- 
fractory phase.  Two  laboratory  examples  may  be  given:  (1)  When 
the  central  end  of  an  afferent  root  is  stimulated  in  the  lumbar  region 
of  the  spinal  cord,  the  movement  produced  is  distinctly  rhythmic  in 
character.  (2)  Upon  stimulating  the  central  end  of  the  sciatic  nerve 
in  a  frog  whose  spinal  cord  has  been  cut  some  days  previously,  a  clonic 


812 


THE    CENTRAL   NERVOUS    SYSTEM 


action  of  the  contralateral  foot  occurs,  and  the  rate  of  the  rhythm  is 
not  affected  by  variation  in  the  frequency  of  the  stimulus. 

In  all  the  above  cases  the  refractory  period  may  be  held  responsible 
for  the  rhythmic  nature  of  the  contraction.  In  other  reflexes  it  exists 
for  another  purpose.  In  the  case  of  the  extensor  thrust,  which  it  will 
be  remembered  is  elicited  by  pressure  applied  to  the  pads  of  the  plantar 
aspect  of  the  foot,  the  momentary  extension  of  the  leg  lasts  only  for  a 
little  less  than  two-tenths  of  a  second,  but  is  followed  by  a  refractory 


Fig.  211. — Tracing  from  the  hind  limb  of  a  spinal  dog  during  the  scratching  movements  pro- 
duced by  applying  stimuli  at  two  skin  points  {A  and  B),  the  application  of  the  stimuli  being  in- 
dicated by  the  signals.  Not  only  were  the  stimuli  applied  at  different  points,  but  at  B  they 
were  of  much  greater  frequency  than  at  A.  Although  there  is  a  slight  change  in  "local  sign,"  it 
will  be  observed  that  there  is  no  alteration  in  rhythm,  indicating  that  this  property  must  be  a 
function  of  the  final  common  path.      (From   Sherrington.) 

period  lasting  nearly  a  whole  second,  during  which  a  second  stimulus 
elicits  no  response.  The  object  of  this  long  refractory  period  is  no  doubt 
that  opportunity  may  be  given  for  the  flexor  muscles  to  perform  the 
contraction  that  would  naturally  ensue  during  the  normal  occurrence 
of  the  extensor  thrust,  as  in  the  act  of  walking.  When  the  animal 
places  his  foot  on  the  ground,  the  sudden  pressure  exerted  on  the  pad 
of  the  foot  immediately  calls  forth  the  extensor  thrust,  by  means  of 


PHYSIOLOGICAL    PROPERTIES   OF    T1IK   SIMPLE    REFLEX    ARC  813 

which  the  weight  of  the  body  is  temporarily  removed  from  the  ground, 
and  the  muscles  perform  the  con  tractions  necessary  to  produce  flexion 
of  the  limb.  Although  the  refractory  period  is  unaffected  by  the  strength 
of  the  stimulus  it  is  very  dependent  upon  the  internal  condition  of  the 
nerve  reflex  arc,  such  as  that  caused  by  changes  in  blood  supply  or  by 
narcosis. 

Reflex  conduction  is  much  less  resistant  than  nerve  conduction  to  various 
conditions  affecting  the  nutritive  condition  of  the  conducting  pathway. 
For  example,  deprivation  of  oxygen  causes  but  slight  interference  with 
the  conduction  along  a  nerve  trunk,  but  very  soon  abolishes  the  spinal 
reflexes.  Even  in  the  frog,  reflex  movements  entirely  disappear  in  thirty 
to  forty-five  minutes  after  the  centers  have  been  rendered  completely 
anemic,  and  in  mammals  they  disappear  in  a  few  minutes.  In  the  ease 
of  drugs  such  as  chloroform,  0.3  per  cent  of  the  drug  may  be  required  to 
abolish  conduction  in  a  nerve,  whereas  a  much  lower  percentage  is  suffi- 
cient to  abolish  it  in  a  reflex  arc. 

From  the  above  differences  in  conduction  in  a  nerve  trunk  and  a  re- 
flex arc,  Ave  learn  many  facts  concerning  the  importance  of  the  latter, 
and  we  further  see  that  the  differences  are  due  very  largely  to  the 
synaptic  connection. 

SUCCESSIVE  DEGENERATION 

Before  concluding  the  subject,  it  may  be  of  interest  to  consider  briefly 
the  method  of  successive  degeneration,  by  which  Sherrington  succeeded 
in  demonstrating  the  exact  tracts  in  the  white  matter  of  the  spinal  cord 
along  which  the  intraspinal  neurons  travel  from  one  segment  to  another. 
This  was  worked  out  in  the  case  of  the  scratch  reflex  in  the  following 
manner:  The  spinal  cord  was  first  of  all  cut  in  the  upper  thoracic  region, 
so  that  degeneration  occurred  in  all  the  descending  tracts  below  the 
level  of  the  section.  In  about  a  year's  time  these  degenerated  tracts  had 
entirely  disappeared,  and  the  debris  of  the  degenerated  fibers  had  been 
replaced  by  cicatricial  tissue,  so  that  a  section  of  the  cord  revealed  noth- 
ing but  healthy  nervous  tissue  with  cicatrices  where  the  degenerated 
tracts  had  existed.  When  at  this  stage  a  second  cut  was  made  across 
the  cord  a  little  lower  than  the  first  one,  further  degeneration  occurred 
involving  those  fibers  whose  centers  were  located  between  the  two  cuts — 
that  is,  the  fibers  coming  from  the  intraspinal  neurons,  with  the  cells  of 
which  the  afferent  nerve  fibers  coming  from  the  skin  of  the  scratch  re- 
flex area  were  connected.  A  section  of  the  cord,  stained  appropriately 
for  degenerated  fibers,  at  this  time  demonstrated  these  fibers  to  exist 
in  the  lateral  column  of  white  matter,  those  that  travel  a  short  distance — 
i.  e.,  between  neighboring  segments — being  near  the  gray  matter,  and 
those  traveling  greater  distances,  towards  the  outside. 


CHAPTER  XCI 
RECIPROCAL  INNERVATION 

Reciprocal  Inhibition. — It  might  appear  that  to  bend  a  joint  or  to 
move  the  eyeball  the  only  muscular  action  required  would  be  contrac- 
tion of  the  muscles  which  flex  the  joint  or  rotate  the  eyeball,  and  that 
the  antagonistic  muscles  would  merely  become  passively  elongated. 
When  we  remember,  however,  that  all  the  muscles  of  the  body  are  or- 
dinarily in  a  condition  of  slight  contraction,  or  tone,  and  that  this  tends 
to  become  increased  when  the  muscles  are  passively  stretched,  then  we 
see  that  for  efficient  movement  there  must  be  inhibition  of  the  tone  of 
the  muscles  which  oppose  those  that  are  contracting.  This  reciprocal 
inhibition,  as  it  is  called,  is  a  very  widespread  function  throughout  the 
animal  body.  Sometimes  it  is  purely  peripheral  in  origin,  as  in  the  claw 
of  the  crayfish,  where  stimulation  of  the  nerve  causes  an  opening  of  the 
claw  due  to  the  contraction  of  one  set  of  muscles  and  the  simultaneous 
inhibition  of  their  antagonists.  Instances  of  peripheral  reciprocal  in- 
hibition in  the  higher  animals  are  not  so  common,  but  are  illustrated  in 
the  case  of  the  myenteric  reflex,  where  it  will  be  remembered  a  contraction  of 
the  intestine  over  a  bolus  of  food  is  accompanied  by  inhibition  in  front  of 
the  bolus.  The  reciprocal  action  in  this  case  is  probably  dependent  on 
the  myenteric  plexus. 

On  the  other  hand,  reciprocal  inhibition  of  central  origin  is  very  com- 
mon in  the  higher  mammalia.  Thus,  in  the  case  of  the  lateral  movement 
of  the  eyes,  if  Ave  cut  the  third  and  fourth  nerves  to  one  eye,  say,  the 
left,  the  external  rectus  of  that  eye  will  alone  be  under  the  control 
of  the  nervous  system,  through  the  sixth  nerve;  nevertheless,  if  we  after- 
ward cause  the  animal  to  look  toward  the  right,  as  by  holding  some  ob- 
ject in  that  direction,  it  will  be  found  that  the  left  eye  as  well  as  the 
right  follows  the  object.  Obviously  there  must  be  an  inhibition  of  the 
external  rectus  muscle  of  the  left  eye,  an  inhibition  which  is  pronounced 
enough  to  bring  about  a  movement  of  the  eyeball,  and  which  exactly  cor- 
responds in  point  of  time  with  the  contraction  of  the  external  rectus  of 
the  right  eye.  This  movement,  due  to  the  atonicity  of  the  external  rec- 
tus, does  not  however  succeed  in  causing  the  eye  to  rotate  beyond  the 
midline  of  the  field  of  vision.  This  is  an  instance  of  a  willed  reciprocal 
inhibition;  i.  e.,  a  reciprocal  inhibition  brought  about  by  stimuli  coming 

814 


RECIPROCAL    INNERVATION  81f> 

from  the  volitional  center  in  the  cerebrum.  The  same  result  may  be 
obtained  by  electric  stimulation  of  the  center  for  eye  movements  on  the 
cerebral  cortex. 

The  most  important  details  concerning  the  mechanism  of  reciprocal 
innervation  have  been  obtained  by  studying  the  flexion  reflex  in  a  spinal 
animal  which  has  completely  recovered  from  shock.  In  such  an  animal 
the  tonus  of  the  extensor  muscles  of  the  knees  is  well  marked.  This 
tonus  is  maintained  by  afferent  impulses  transmitted  to  the  spinal  cord 
from  receptors  situated  in  the  muscles,  and  its  degree  of  intensity  can 
be  estimated  by  the  briskness  of  the  knee-jerk,  which,  it  will  be  remem- 


Fig.  212. — Record  from  myograph  connected  with  the  extensor  muscle  of  the  knee.  During 
the  time  marked  by  the  lower  signal,  the  skin  of  the  opposite  foot  was  stimulated,  thus  causing 
the  crossed  extension  reflex.  While  still  maintaining  this  stimulation,  faradic  shocks  were  ap- 
plied to  the  skin  of  the  foot  of  the  same  side  (as  indicated  by  the  upper  signal),  with  the  result 
that   immediate   inhibition   of   the    contracted   extensor   occurred.      (From    Sherrington.) 

bered,  is  elicited  by  tapping  the  patellar  tendon,  and  consists  of  a  sud- 
den extension  movement  at  the  knee  joint.  By  observing  the  briskness 
of  the  knee-jerk  we  are  therefore  enabled  to  form  an  estimate  of  the 
tonicity  of  the  extensor  muscles;  and  if  after  doing  so  we  throw  the 
flexors  which  are  their  antagonists  into  activity  by  eliciting  the  flexion 
reflex,  the  knee-jerk  will  be  found  much  less  active.  If  we  prevent  the 
flexors  from  acting  on  the  knee  joint  and  the  leg  is  held  in  an  extended 
position,  irritation  of  the  skin  of  the  leg  will  cause  the  flexion  of  the 


816  THE    CENTRAL    NERVOUS   SYSTEM 

disconnected  hamstring-  muscles  simultaneously  with  a  visible  relaxation 
of  the  extensors  (Fig.  212).  If  the  leg  is  held  properly,  this  relaxation  may 
be  marked  enough  to  cause  a  slight  flexion  at  the  joint;  and  in  any  case, 
if  the  knee-jerk  is  regularly  elicited  by  equal  taps  applied  to  the  patellar 
tendon,  it  will  be  found  that,  while  the  flexion  is  being  produced,  the 
knee-jerk  is  very  much  less  than  normal,  if  not  entirely  absent,  thus  in- 
dicating that  the  tone  of  the  extensor  muscles  is  diminished.  This  ex- 
periment is  very  striking  when  performed  on  a  decerebrate  animal,  in 
which,  as  we  shall  see,  the  extensor  muscles  of  the  limb  are  in  a  per- 
manent state  of  hypertonicity  (Fig.  213). 

Before  it  is  permissible  to  conclude  that  this  reciprocal  inhibition  is  a 
necessary  event  in  the  movement  of  a  joint,  Ave  must  however  show  that 
it  occurs  at  exactly  the  same  time  as  the  flexion  of  the  antagonist.  Sher- 
rington has  succeeded  in  doing  this  in  a  considerable  variety  of  experi- 


/Ant  Crural  N. 
Femoralis) 


Sciatic  N. 
(Ischiddicus) 


Fig.    213. — Diagram   showing   the    muscles   and    nerves   concerned    in    reciprocal    innervation.      (After 

Sherrington.) 

ments,  one  of  which  we  may  cite  here.  If,  in  a  spinal  dog,  the  tendons 
of  the  flexor  muscles  of  the  knee  joint  of  one  hind  limb  and  the  ex- 
tensor tendons  of  the  opposite  limb  are  cut,  then  the  former  limb  will 
be  unable  to  flex  properly,  but  will  nevertheless  exhibit  reciprocal 
inhibition  of  the  intact  extensor  muscle,  while  the  latter  limb  will  flex, 
but  require  passive  extension  to  bring  it  back  to  its  old  position.  If 
suitable  stimuli  are  simultaneously  applied  to  the  skin  of  both  legs  and 
the  movements  of  th,e  isolated  muscles  recorded,  the  onset  of  inhibition 
of  the  intact  extensor  of  the  one  leg  and  the  contraction  of  the  flexors 
of  the  opposite  leg  will  be  found  to  agree  with  regard  to  latent  periods, 
strength  of  required  stimulus,  summation  and  indeed  all  the  other  phys- 
iologic properties  of  reflex  action. 

Reciprocal  innervation  can  also  be  demonstrated  by  stimulating  the 
central  end  of  suitable  afferent  nerves — that  is,  certain  afferent  nerves 


RECIPROCAL    INNERVATION 


817 


Fig.  214. — Reciprocal  innervation.  Tracings  made  by  myographs  connected  with  E,  an  ex- 
tensor muscle  (vastus  crureus),  and  F,  a  flexor  muscle  (semitendinosus),  of  a  decerebrate  cat. 
At  signal  /  the  contralateral  peroneal  nerve  was  excited,  causing  contraction  of  the  flexors  and  in- 
hibition of  the  tone  of  the  extensors.  At  signal  //  the  flexors  were  again  thrown  into  contraction  by 
exciting  the  contralateral  peroneal  nerve,  and  (without  removing  this  stimulus)  the  homolateral 
peroneal  nerve  was  excited  (as  shown  in  the  lower  signal),  with  the  result  that  the  contraction 
of  the  flexors  was  inhibited  at  the  same  time  that  the  extensors  contracted.  On  removal  of  the 
latter  stimulus,  the  former  one  reasserted  its  influence.  This  experiment  demonstrates  very  clearly 
the   accurate   coincidence    of   the   reciprocal   action.      (From    Sherrington.) 


-]- 


THE    CENTRAL    NERVOUS    SYSTEM 


acting  on  the  same  groups  of  neurons  will  produce  a  flexion  reflex,  others 
an  extension  reflex;  thus,  stimulation  of  the  contralateral  peroneal  nerve 
produces  a  flexion  reflex  of  the  hind  limb  (excitatory  for  flexors,  in- 
hibitory for  extensors),  whereas  stimulation  of  the  homolateral  peroneal 
nerve  produces  an  extension  (inhibitory  for  flexors,  excitatory  for  ex- 
tensors). By  taking  advantage  of  these  facts  further  proof  may  be 
supplied  that  inhibition  and  contraction  occur  simultaneously,  as  shown 
in  Fig.  214. 

It  is  impossible  to  demonstrate  any  trace  of  inhibition  of  the  skeletal 


Fig.  215. — Sherrington's  diagram  illustrating  the  mechanism  of  reciprocal  innervation.  The 
afferent  fibers  (5)  from  the  skin  of  the  leg  and  (5')  from  the  flexor  muscles  of  the  knee  (in 
hamstring  nerve)  pass  to  tEe  spinal  cord,  where  each  gives  off  a  branch  which  divides  into  two 
others,  of  which  one  in  each  case  goes  to  a  motor  neuron  of  the  extensor  muscles  (£)  and  the 
other  to  a  motor  neuron  (5)  of  the  flexor  muscles  (F).  Branches  also  pass  across  the  median 
line  to  similar  motor  neurons  on  the  opposite  side  of  the  cord.  As  indicated  by  the  plus  and 
minus  signs,  the  afferent  stimuli  either  stimulate  or  inhibit  the  activities  cf  the  motor  neurons, 
the  determination   of   the   exact   effect  beinj  a  function  of  the  synapsis.      (From    Sherrington.) 

muscles  by  stimulation  of  their  motor  nerves,  thus  indicating  that  in- 
hibition is  dependent  upon  the  nerve  center.  Furthermore,  since  inhibition 
occurs  along  with  flexion  of  the  antagonistic  muscle,  we  must  assume 
that  the  afferent  impulse  on  entering  the  spinal  cord  divides  into 
two  branches,  one  going  to  one  motor  neuron  so  as  to  excite  it,  the  other 
to  another  neuron  so  as  to  inhibit  the  tonic  stimuli  which  it  is  con- 
stantly sending  to  the  muscles  (Fig.  215). 

Since  the  seat  of  the  inhibition  is  in  the  nerve  center,  it  is  to  be  ex- 
pected that  impulses  transmitted  from  other  parts  of  the  nervous  system 


RECTPBOC  \L    i\\l  OVATION  819 

than  tlic  particular  level  of  that  reflex,  will  also  be  able  to  induce  the 
inhibition.  In  the  case  of  the  decerebrate  cat  this  can  be  demonstrated 
by  stimulation  of  the  lateral  columns  of  the  spinal  cord;  inhibition  of 
the  extensor  muscles  of  the  elbow  joint  occurs,  which  is  all  the  more 
marked  because  in  such  a  preparation  these  muscles  are  in  a  state  of 
hypertonicity.  We  shall  see  later  also  that  through  the  pyramidal  tract 
impulses  may  descend  from  the  cerebrum  which  exercise  a  marked  in- 
hibitory influence  over  the  reflex  activities  of  the  cord.  Similarly  the 
inhibition  itself  may  be  terminated  by  impulses  from  other  sources,  and 
the  motor  neuron  thus  thrown  from  a  state  of  inhibition  into  one  of  ex- 
citation. This  fact  can  perhaps  best  be  demonstrated  by  exciting  the 
central  end  of  the  homolateral  peroneal  nerve  (which  produces. a  reflex 
extension  of  the  leg)  while  the  leg  is  being  held  in  a  flexed  position  by 
stimulation  of  the  contralateral  peroneal  nerve.  This  will  be  clear  from  a 
study  of  Fig.  214. 

Such  alternating  excitation  and  inhibition  of  an  active  motor  neuron 
serve  to  make  it  possible  for  rhythmic  discharges  to  occur  through  the 
neuron,  as  in  the  action  of  the  muscles  of  the  leg  in  walking  or  during 
the  scratching  movement.  In  order  to  insure  that  the  same  final  com- 
mon path  may  be  occupied  at  one  time  by  but  one  kind  of  stimulus,  either 
inhibitory  or  excitatory,  it  is  further  of  importance  that  the  after-dis- 
charge (see  page  810)  of  the  first  stimulus  should  be  capable  of  imme- 
diate inhibition ;  otherwise,  while  one  reflex  was  in  progress,  it  would  be 
impossible  to  start  another  of  a  different  type  employing  the  same  motor 
neuron  without  confusion  of  movement.  That  this  occurs  can  be  demon- 
strated in  the  case  of  the  after-discharge  of  the  flexion  reflex  by  stimula- 
tion of  the  proper  afferent  nerve. 

In  view  of  all  these  .facts  it  is  probable  that  the  seat  of  the  reciprocal 
innervation  is  at  or  about  the  synapsis.  In  other  words,  the  synapsis  at 
the  termination  of  one  collateral  will  allow  a  stimulating  impulse  to  pass 
to  the  cells  of  one  motor  neuron,  whereas  that  at  the  end  of  another  col- 
lateral of  the  same  afferent  fiber  will  allow  an  inhibiting  impulse  to  pass 
to  an  antagonistic  motor  neuron,  these  conditions  being,  however,  readily 
interchangeable  and  thus  making  even  rapid  rhythmic  contraction  and 
relaxation  a  possibility. 

The  Action  of  Strychnine  and  Tetanus  Toxin  on  Reciprocal  Inhibition 

Under  certain  conditions  reciprocal  action  may  fail  to  occur,  as,  for 
example,  at  certain  stages  of  strychnine  poisoning  and  during  the  action 
of  tetanus  toxin.  In  order  to  demonstrate  this  failure  of  reciprocal  ac- 
tion, it  is  necessary  to  examine  muscles  which  act  on  one  joint  only,  and 


820  THE    CENTRAL   NERVOUS   SYSTEM 

to  observe  their  behavior  when  an  afferent  nerve  is  stimulated  which  un- 
der ordinary  conditions  would  throw  them  into  inhibition.  Such  a 
preparation  can  be  obtained  in  the  hind  limb  of  a  dog  by  cutting  all  the 
muscles  that  act  on  the  knee  joint  except  the  vastus  crureus,  which  in  a 
normal  animal  invariably  undergoes  inhibition  when  the  central  end  of 
the  internal  saphenous  nerve  is  stimulated.  If  a  suitable  dose  of  strych- 
nine is  injected,  it  will  be  found  that  stimulation  of  the  internal  sapbenous 
nerve,  in  place  of  inhibition,  causes  contraction  of  the  vastus  crureus 
muscle.     The  same  result  is  obtained  by  injection  of  tetanus  toxin. 

The  failure  of  the  reflex  inhibition  explains  the  symptoms  produced 
by  these  substances.  It  explains,  for  example,  the  Avell-known  rigidly 
extended  condition  of  the  limbs  in  strychnine  poisoning,  and  the  dis- 
tressing symptom  of  lockjaw  in  tetanus  infection.  In  this  latter  con- 
dition the  sufferer  is  subjected  to  extreme  torture  with  every  endeavor 
that  he  makes  to  open  the  jaw  for  the  purpose  of  taking  food  or  drink. 
Firmer  closure  is  the  result  because  the  normal  inhibition  of  the  temporal 
and  masseter  muscles  does  not  occur,  but  instead  they  become  excited 
and  the  jaw  all  the  more  firmly  closed.  Not  only  does  the  inhibition  fail 
to  occur,  but  the  above  muscles  are  usually  in  a  state  of  constant  hy- 
perexcitability,  which  it  is  impossible  for  the  patient  to  restrain ;  indeed, 
whenever  he  attempts  to  do  so  the  opposite  occurs  and  the  excitation 
becomes  heightened.  Chloroform  acts  on  reciprocal  innervation  in  an 
opposite  way  from  strychnine  and  tetanus ;  namely,  it  paralyzes  the  ex- 
citation of  the  contracting  muscles. 

Finally,  it  must  be  pointed  out  that  this  mechanism  of  reciprocal  in- 
nervation is  I)y  no  means  confined  to  the  voluntary  muscles.  We  have 
already  seen  that  it  occurs  in  the  case  of  the  myenteric  reflex.  It  is  also 
a  most  important  function  in  the  innervation  of  the  blood  vessels,  dilata- 
tion in  one  vascular  area  being  accompanied  by  constriction  in  another. 
These  facts  have  been  already  sufficiently  dwelt  upon  elsewhere  (page 
243).  Sometimes  also  we  may  have  reciprocal  action  between  differently 
acting  nervous  mechanisms,  as  for  example  in  the  case  of  the  submaxil- 
lary glands,  which  respond  to  stimulation  of  the  chorda  tympani  nerve 
by  dilatation  of  the  blood  vessels,  an  inhibition  of  their  tone  occurring 
along  with  stimulation  of  the  activity  of  the  gland  cells. 


CHAPTER  XCII 

INTERACTION  AMONG  REFLEXES 

A  single  reflex  acting  independently  of  the  rest  of  the  central  nervous 
system  does  not  really  occur.  An  afferent  impulse  on  entering  the  cord 
spreads  so  as  to  involve  a  large  variety  of  motor  neurons,  each  of  which 
may,  however,  be  excited  through  other  afferent  fibers  arriving  either 
from  other  receptors  or  from  higher  nerve  centers.  The  motor  neuron 
itself  may  therefore  be  a  pathway  occupied  at  different  times  by  very 
different  types  of  nerve  impulse.  Hence  it  is  appropriately  called  the 
final  common  path,  and  its  activity  at  any  moment  must  depend  on  the 
nature  of  the  various  afferent  impulses  that  are  transmitted  to  it  through 
the  synapses.  In  other  words,  an  entering  afferent  fiber  must  communi- 
cate in  the  cord  with  internuncial  paths  which  are  available  in  various 
degrees  to  other  afferent  fibers.  Since  it  is  through  internuncial  paths 
that  the  impulse  is  transmitted  to  the  final  common  path,  it  is  obvious 
that,  if  afferent  impulses  in  several  of  these  paths  were  competing  at 
the  same  time  for  the  possession  of  the  final  common  path,  confusion  of 
movement  would  result  unless  some  provision  were  made  whereby  only 
one  kind  of  stimulus  could  be  transmitted  at  one  time.  "One  kind  of 
stimulus  must  be  inhibited  and  the  other  facilitated  in  its  occupancy  of 
the  final  common  path." 

To  understand  the  nature  of  this  integration  of  the  central  nervous 
system,  it  is  therefore  necessary  for  us  to  consider  the  factors  which  de- 
termine which  of  two  competing  afferent  impulses  shall  obtain  possession 
of  the  final  common  path.  Let  us  take  the  competition  between  the  flexion 
reflex  and  the  scratch  reflex  of  the  spinal  dog.  If  we  elicit  the  scratch 
reflex  and,  while  it  is  in  progress,  apply  some  nocuous  stimulus  to  the 
skin  of  the  hind  leg  and  thus  induce  the  flexion  reflex,  it  will  be  found 
that  the  scratching  movement  subsides  and  the  flexion  movement  comes 
on  without  any  overlapping  or  confusion.  If,  however,  the  stimulus 
responsible  for  the  scratching  movement  is  a  strong  one,  and  that  ap- 
plied to  the  skin  of  the  hind  leg  a  feeble  one,  then  the  displacement  may 
not  occur  (see  Fig.  216). 

In  considering  this  integration  of  reflexes,  as  it  is  called,  we  must  dis- 
tinguish between  those  that  are  allied  and  those  that  are  antagonistic, 
and  we  must  further  distinguish  between  reflexes  that  are  simultane- 

821 


822  THE    CENTRAL    NERVOUS   SYSTEM 

ously  competing  for  the  same  final  common  path  and  those  which  occupy 
it  successively. 

INTEGRATION  OF  ALLIED  REFLEXES 

Perhaps  the  simplest  experiment  to  show  this  is  performed  by  using 
the  scratch  reflex.  The  skin  area  from  which  this  reflex  can  be  elicited 
is  very  widespread  (see  Fig.  217),  the  type  of  reflex  produced  from  any 
given  area  being  in  general  the  same,  although  "the  local  sign" — that 
is,  the  point  at  which  the  animal  scratches — will  vary  according  to  the 
point  stimulated.  If  then  we  take  point  A  in  the  reflex  scratch  area 
and  apply  to  it  a  stimulus  which  is  just  inadequate  to  produce  any  reflex 
at  all,  and  then,  while  this  stimulus  is  still  in  progress,  apply  a  similar 
subliminal  stimulus  to  point  B  a  little  removed  from  it,  the  two  sub- 


Fig.  216. — Diagram  showing  the  reflex  arcs  involved  in  the  scratch  reflex.  Ra  and  R(3  represent 
the  afferent  neurons  connected  with  hairs  on  the  skin  of  the  hack  and  flank.  The  afferent  im- 
pulses are  transmitted  by  these  fibers,  and  on  entering  the  corresponding  segments  of  the  spinal 
cord  terminate  by  synapses  on  cells  of  the  internuncial  neurons,  whose  arrows  Pa  and  Pj3  travel 
down  in  the  lateral  columns  to  terminate  similarly  around  the  cells  of  the  motor  neurons  that 
innervate  the  muscles  of  the  hind  limb.  Since  afferent  impulses  coming  from  elsewhere,  par- 
ticularly from  the  skin  of  the  leg  (R  and  L),  also  terminate  on  these  neurons  and  may  excite 
them  to  a  different  type  of  action,  the  motor  neuron  is  called  the  final  common  path  (.F.C.). 
(From   Sherrington.) 

liminal  stimuli  will  become  effective  and  produce  a  typical  scratching 
movement.  In  other  words,  the  subliminal  stimulus  of  point  A  be- 
comes added  on  the  final  common  path  with  the  subliminal  stimulus  of 
point  B;  the  one  has  reinforced  the  other  and  produced,  therefore,  a 
simultaneous  integration  of  allied  reflexes. 

The  receptors  from  which  these  mutually  reinforcing  impulses  are  re- 
ceived need  not,  as  in  the  above  example,  be  of  the  same  kind,  similar 
results  being  obtained  by  stimulation  of  receptors  of  widely  different 
kinds,  such  as  exteroceptors  and  proprioceptors  (see  page  788).  For  ex- 
ample, if  a  stimulus  inadequate  to  elicit  a  flexion  reflex  is  applied  to  the 
skin  of  the  leg,  and  another  stimulus,  itself  also  inadequate,  is  ap- 
plied to  the  central  end  of  some  deep  afferent  nerve  in  the  same  leg, 
then  the  two  subliminal   stimuli  will  become  effective  in  producing  a 


INTERACTION    AMONG    REFLEXES 


823 


flexion  movement.     Nevertheless,  the  more  closely  allied  the  receptors 
are  to  one  another,  the  more  easily  does  summation  occur. 

The  mutual  reinforcement  of  allied  reflexes  lasts  for  a  short  time  after 
the  stimulation  has  been  removed,  the  phenomenon  being  now  known  as 
successive  integration  of  allied  reflexes.  It  can  be  illustrated  also  in  the 
case  of  the  scratch  reflex.  If  point  A  on  the  skin  area  is  excited  with  a 
stimulus  that  in  itself  would  be  inadequate,  immediately  after  an  effec- 
tive stimulus  has  been  discontinued  at  point  B,  then  the  scratch  move- 
ment will  be  kept  up  smoothly  although  it  will  of  course  become  modi- 
fied in  local  sign.  For  the  same  reason,  a  moving  stimulus  applied 
to  the  scratch  area  is  far  more  effective  than  a  stationary  stimulus  ap- 
plied over  the  same  extent  of  area.  In  such  a  case  the  stimulus  that 
excites  a  reflex  tends  by  its  occupancy  of  the  nervous  pathway  to  facili- 


l'ig.   217. — Showing  region   of   body   of  dog   from  which  the   scratch   reflex   can   be   elicited. 

Sherrington.) 


(From 


tate  the  spread  along  the  same  pathway  of  succeeding  allied  stimuli; 
towards  such  it  lowers  the  threshold  of  excitability  of  the  reflex  arc. 

This  phenomenon  is  also  often  called  immediate  induction,  and  it  is 
by  no  means  confined  to  the  spinal  cord.  It  is  well  illustrated,  for  ex- 
ample, in  the  case  of  vision.  If  a  thin  line  drawn  on  a  white  card  be 
looked  at  so  that  it  falls  on  the  edge  of  the  receptive  field  of  the  retina, 
it  will  not  be  seen  so  well  as  a  dot  of  similar  width  which  is  moved 
1  hrough  the  same  distance  as  the  line. 

From  these  facts  we  see,  therefore,  that,  when  two  allied  impulses  are 
being  transmitted  to  the  final  common  path,  the  one  is  likely  to  reinforce 
the  other,  and  that  this  tendency  to  reinforce  the  allied  impulse  is  main- 
tained for  a  brief  period  of  time  after  the  impulse  has  been  removed.  We 
may  now  proceed  to  consider  the  factors  which  will  become  operative 
in  determining  to  which  of  two  competing  or  antagonistic  reflexes  the 
final  common  path  will  become  available. 


824  THE    CENTRAL   NERVOUS   SYSTEM 

Integration  of  Antagonistic  Reflexes. — Although  the  phenomenon  of 
immediate  induction  encourages  integration  of  allied  reflexes,  yet  it  is 
frequently  succeeded  by  one  of  successive  induction,  in  which  just  the 
opposite  conditions  occur;  the  resistance  in  the  reflex  pathway  becomes 
lowered  for  a  type  of  movement  antagonistic  to  that  which  first  occu- 
pied the  reflex.  To  understand  clearly  what  relationship  this  bears  to 
immediate  induction,  it  may  be  well  to  take  the  instances  in  which  these 
phenomena  apply  in  the  case  of  vision.  Wjhen  the  eye,  after  darkness, 
is  suddenly  directed  to  a  light  and  then  closed,  there  remains  a  bright 
image  (positive  after-effect)  of  the  light;  but  if  the  light  is  looked  at 
for  some  time,  then  on  closing  the  eyes  it  will  be  seen  as  a  dark  pat- 
tern (negative  after-effect).  In  the  former  instance  Ave  have  an  exam- 
ple of  immediate  induction,  in  the  latter,  one  of  successive  induction. 

In  the  spinal  animal  successive  induction  is  demonstrated  with  equal 
ease  by  using  two  reflexes  that  are  of  a  more  or  less  antagonistic  charac- 
ter— for  example,  the  flexion  reflex  and  the  knee-jerk,  or  better  still 
the  crossed  extension  reflex  and  the  flexion  reflex.  If  we  elicit  the  knee- 
jerk  in  a  spinal  dog  at  regular  intervals,  with  stimuli  of  equal  intensity, 
the  extension  movements  (the  kicks)  will  be  approximately  equal.  If 
now  we  apply  a  nocuous  stimulus  to  the  skin  of  the  foot  and  so  throw 
the  leg  into  flexion,  it  will  be  found,  after  the  flexion  movement  has  dis- 
appeared, that  the  knee-jerk  is  much  more  pronounced  than  previously. 
Similarly,  if  we  elicit  the  crossed  extension  reflex  by  nocuous  stimuli 
of  equal  intensity  applied  to  the  opposite  limb,  the  extension  movements 
will  be  approximately  equal.  By  now  throwing  the  limb  exhibiting  them 
into  the  flexion  reflex,  the  extensor  movements  will  of  course  disappear, 
but  after  the  flexion  has  been  discontinued,  they  will  reappear  with 
marked  intensity. 

These  facts  show  us,  then,  that  after  the  final  common  path  has  been 
occupied  by  a  reflex  of  one  type,  it  becomes  more  available  to  a  reflex 
of  an  opposite  type.  In  other  words,  it  is  evident  that  if  the  two  op- 
posite reflexes  are  constantly  competing  with  each  other  for  possession 
of  the  final  common  path,  they  will  tend  alternately  to  occupy  it,  thus 
bringing  about  a  rhythmic  movement.  Such  is  the  mechanism  involved 
in  walking:  the  leg  is  lifted  from  the  ground  (flexion  reflex)  ;  it  is  then 
brought  on  the  ground,  and  the  mechanical  push  given  to  the  plantar 
surface  of  the  foot  brings  out  the  extensor  thrust,  the  appearance  of 
which  is  greatly  facilitated  by  the  fact  that  immediately  before  the  flexion 
reflex  occupied  the  final  common  path. 

Other  Factors  Which  Determine  the  Occupancy  of  the  Final  Common 
Path. — Besides  immediate  and  successive  induction,  several  other  fac- 
tors affect  the  relative  availability  of  the  reflexes  to  afferent  stimulation. 


INTERACTION    AMONG    REFLEXES  825 

Important  among  these  is  fatigue  of  the  reflex  arc  for  a  particular  kind 
of  stimulus.  Many  characteristics  differentiate  reflex  fatigue  from  fatigue 
of  a  nerve  ;is  observed  in  an  isolated  nerve-muscle  preparation.  The 
most  important  of  these  distinguishing  features  are  as  follows:  (1) 
The  fatigue  comes  on  intermittently;  thus,  when  the  flexion  reflex  is 
persistently  elicited,  the  first  sign  of  fatigue  is  an  irregular  decline  in 
the  flexion  movement  followed  by  its  entire  disappearance  for  a  short 
time.  These  lapses  become  more  and  more  frequent,  until  at  last  com- 
plete fatigue  sets  in  and  no  flexion  occurs.  (2)  Reflex  fatigue  soon 
passes  off.  (3)  It  appears  earlier  for  weak  than  for  strong  stimuli.  (4) 
The  movement  produced  by  the  reflex  action  may  also  change  in  character 
during  reflex  fatigue;  thus,  the  beat  of  the  scratch  reflex  may  become 
slower  and  less  steady  and  the  foot  be  less  accurately  directed  to  the 
spot  stimulated.  The  locus  of  the  fatigue  in  the  reflex  arc  can  not 
be  the  motor  neuron  itself,  for,  after  this  has  been  completely  fatigued 
by  stimulation  of  the  scratch  area,  the  same  muscles  may  quite  readily 
be  thrown  into  a  perfectly  normal  flexion  reflex  by  stimulation  of  the 
skin  of  the  hind  leg. 

It  is  evident  that,  when  two  reflexes  are  competing  with  each  other 
for  possession  of  the  same  final  common  path,  the  one  that  becomes  fa- 
tigued will  be  mastered  by  the  other,  especially  since  at  the  same  time 
successive  induction  will  be  well  developed.  Thus,  ordinarily  the  scratch 
reflex  is  much  less  readily  elicited  than  the  flexion  reflex,  and  if*  both 
are  excited  at  the  same  time  the  latter  will  prevail;  but  if  the  flexion  re- 
flex is  kept  up  until  it  shows  signs  of  fatigue,  then  by  simultaneous 
excitation  of  both  reflexes  the  scratch  reflex  will  obtain  the  mastery. 

Another  important  factor  is  the  relative  strength  of  the  competing 
impulses.  This  depends  partly  on  the  nature  of  the  reflex  and  partly  on  the 
intensity  of  the  stimulus.  Regarding  the  nature  of  the  reflex,  it  is  important 
to  remember  that  crossed  reflexes  are  usually  less  easily  obtained  than  homo- 
lateral ones,  but  of  still  greater  importance  is  the  species  of  reflex — 
that  is,  whether  flexion,  scratch,  extension,  etc.  The  reflex  movements 
produced  by  nocuous  stimuli  (nociceptive  reflexes)  always  take  precedence 
of  those  produced  by  other  kinds  of  stimuli;  or,  to  put  it  in  other 
words,  "nociceptive  reflexes  are  prepotent  in  their  occupancy  of  the 
final  common  path" — (Sherrington18). 

The  best  known  example  of  a  nociceptive  reflex  is  the  flexion  reflex. 
Its  movement  is  one  produced  with  the  intention  of  removing  the  stimu- 
lated portion  of  the  body  from  the  source  of  the  stimulus,  all  stimuli  which 
produce  it  being  such  as  would  elicit  pain  in  an  intact  animal,  or  if  per- 
sisted in  cause  some  damage  to  the  skin.  In  contrast  to  such  nociceptive 
reflexes  we  may  take  those  which  are  concerned  in  maintaining  the  cen- 


826  THE    CENTRAL   NERVOUS    SYSTEM 

ter  of  gravity  of  the  body — postural  reflexes,  as  they  are  called.  The 
best  type  of  this  reflex  is  the  knee-jerk,  another  good  example  being  the 
extensor  thrust.  The  scratch  reflex  contains  a  certain  element  of  the 
nociceptive  in  it,  and  of  the  simpler  reflexes  it  comes  second  in  its  claim 
on  the  final  common  path.  In  brief,  then,  in  reflexes  which  in  an  intact 
animal  would  cause  the  sensation  of  pain  and  probably  some  reflex  ac- 
tivity of  the  vocal  organs,  we  get  in  the  spinal  animal  a  reflex  flexion 
movement  of  the  part  stimulated  with  the  evident  object  of  removing 
that  part  from  the  stimulating  agency.  This  reflex  flexion  secures  pos- 
session of  the  final  common  path  whatever  other  reflex  may  at  the  time 
be  occupying  it.  Thus,  if  the  animal  is  scratching  itself  and  something 
occurs  to  hurt  its  foot,  then  immediately  the  scratching  movement  will 
give  place  to  one  of  flexion,  and  so  on. 

Some  integration  between  distant  reflex  arcs  in  the  nervous  system 
is  to  a  certain  extent  an  application  of  the  principle  of  reciprocal  in- 
hibition of  the  muscles  moving  a  joint.  In  this  broader  integration  the 
inhibition  affects  more  removed  fields  of  reflex  activity  so  as  to  harmonize 
the  activities  of  one  part  of  the  animal  with  those  of  every  other  part. 

The  manner  in  which  the  stimulation  may  spread  along  the  various 
available  pathways  also  depends  on  the  strength  of  the  afferent  im- 
pulses. If  a  very  feeble  stimulus  is  applied  to  the  skin  of  the  leg  in  a 
spinal  animal,  the  reflex  Mill  be  represented  only  by  a  slight  contraction 
of  the  inner  ends  of  the  hamstring  muscles.  As  the  stimulus  is  increased 
in  strength  the  reaction  will  spread,  until  at  last  it  involves  all  the 
flexors  in  contraction  and  the  antagonistic  extensors  in  inhibition.  If  it  is 
still  further  increased,  the  flexion  movement  will  be  accompanied  by  an 
extension  of  the  muscles  of  the  opposite  hind  limb — the  crossed  exten- 
sion reflex.  Further  increase  of  the  stimulus  will  cause  the  reflex  move- 
ment to  spread  to  the  anterior  extremities,  involving,  first  of  all,  the 
fore  limb  of  the  same  side  (extension  at  the  elbow  and  contraction  at 
the  shoulder),  and  then  that  of  the  opposite  side  (flexion  at  the  elbow 
and  extension  at  the  wrist).  A  very  powerful  stimulus  applied  to  the 
hind  limb  will  even  spread  to  other  more  distant  muscular  groups,  such 
as  those  of  the  neck,  causing  a  turning  of  the  head  to  the  side  stimu- 
lated, opening  the  mouth,  etc. 

This  spread  or  irradiation  of  the  reflex  in  the  spinal  cord  can  not  be 
entirely  explained  on  anatomic  grounds,  and  must  depend,  therefore, 
upon  varying  resistance  to  the  flow  of  the  afferent  impulse  to  different 
motor  neurons,  some  of  which  it  excites  while  others  it  inhibits. 

The  necessity  for  adjustable  resistance  to  the  .transmission  of  different 
afferent  stimuli  on  to  the  final  common  path  becomes  evident  when  we 
remember  that,  not  only  are  there  about  five  times  as  many  fibers  en- 


INTERACTION   AMONG   REFLEXES  827 

tering  the  cord  as  motor  fibers  leaving  it,  but  also  that  each  afferent 
fiber,  after  its  entry  to  the  cord,  gives  off  several  collaterals,  each  of 
which  runs  to  some  nerve  center  in  the  cord  (see  Fig.  207). 

Certain  conditions  may  break  down  the  path  along  which  the  impulse 
passes;  for  example,  at  a  certain  stage  in  the  action  of  strychnine  all 
pathways  become  opened  up,  so  that  the  reflexes  which  ordinarily  do  not 
occur  together,  act  simultaneously,  with  the  result  that  a  typical  convul- 
sive movement  is  produced.  Strychnine,  as  we  have  already  seen,  also 
interferes  with  the  sorting  out  of  the  impulses  into  inhibitory  and  ex- 
citatory, so  that  no  reciprocal  action  occurs. 


CHAPTER  XCIII 

THE  TENDON  JERKS;  SENSORY  PATHWAYS  IN 
SPINAL  CORD 

Certain  responses  are  of  importance  largely  because  of  their  clinical 
application.  Of  greatest  interest  in  this  connection  are  the  tendon  jerks. 
The  location  of  the  sensory  pathways  in  the  spinal  cord  also  demands  at- 
tention. 

The  Tendon  Jerks. — One  of  the  most  important  reflexes  for  diagnostic 
purposes  is  that  known  as  the  knee-jerk,  which  is  elicited  in  man  by  ap- 
plying a  smart  tap  to  the  patellar  tendon  of  a  person  who  is  sitting  on 
a  high  stool  or  table  so  that  the  joint  is  passively  flexed  and  the  leg 
hangs  loosely  from  the  knee  joint.  In  this  position  the  extensor  muscles 
are  put  slightly  on  the  stretch,  and  when  the  patellar  tendon  is  struck, 
these  muscles  contract  and  cause  the  leg  to  become  extended  as  in  kick- 
ing. This  reflex,  as  we  have  seen,  is  also  readily  elicited  in  spinal 
animals.  Its  importance  from  a  clinical  standpoint  depends  on  the 
fact  that  it  may  be  altered  not  only  in  various  general  conditions  of  the 
body,  but  also  when  any  pathologic  condition  disturbs  the  continuity  of 
the  reflex  arc  concerned  in  maintaining  the  tonicity  of  the  extensor  mus- 
cles of  the  thigh.  The  centers  involved  in  this  arc  are  situated  about 
the  third  or  fourth  lumbar  segment,  and  the  afferent  impulses  come 
partly  from  the  antagonistic  flexor  muscles  and  partly  from  the  extensor 
muscle  itself.  Abolition  of  the  reflexes  may  therefore  be  produced  either 
by  neuritis  involving  the  afferent  fibers  or  myelitis  affecting  the  gray 
matter  of  the  cord.  That  certain  of  the  afferent  impulses  come  from  the 
hamstring  muscles  is  shown  by  the  fact  that  when  the  central  end  of  the 
cut  motor  nerve  of  the  extensor  muscles  is  stimulated  electrically,  the 
knee-jerk  becomes  much  less  evident,  a  result  which  is  also  obtained  by 
massaging  the  muscles. 

Although  such  facts  show  clearly  that  the  knee-jerk  is  of  reflex  na- 
ture, yet  there  are  difficulties  in  explaining  the  exact  mechanism  by 
which  the  tap  to  the  tendon  produces  the  muscular  contraction.  The 
chief  difficulty  is  in  accounting  for  the  promptness  with  which  the  contrac- 
tion occurs,  the  latent  period  being  very  much  shorter  than  that  of  such 
reflexes  as  the  flexion  or  even  the  conjunctival.  The  total  latent  period 
of  the  knee-jerk,  as  judged  by  the  time  elapsing  between  applying  a  tap 


TENDON    JERKS;    SENSORY    PATHWAYS   IN    SPINAL    f'ORD  829 

to  the  tendon  and  the  electrical  response  observed  in  the  vastus  interims 
muscle  by  the  string  galvanometer,  was  found  by  Jolly  in  the  spinal  cat 
to  be  0.0055  of  a  second,  whereas  measured  in  the  same  way  the  latent 
period  of  the  flexion  reflex  was  found  to  be  just  twice  as  long ;  i.  e.,  0.0106  of 
a  second.  These  differences  were  explained  by  Jolly  as  indicating  that 
the  knee-jerk  is  a  simple  reflex,  involving  but  two  neurons,  whereas  the 
flexion  reflex  involves  three  and  therefore  has  twice  as  long  a  latent 
period.  By  subtracting  from  the  total  latent  period  the  time  occupied 
in  the  transmission  of  the  impulse  along  the  nerves  and  the  time  lost  at 
the  afferent  and  efferent  nerve  endings,  we  secure  a  figure  giving  the  time 
lost  in  the  synapses  between  the  neurons.  This  synapse  time,  as  it  is 
called,  was  found  by  Jolly  to  be  0.0021  of  a  second  for  the  knee-jerk 
and  0.0043  of  a  second  for  the  flexion  reflex.7  Snyder  obtained  somewhat 
similar  results  in  man  by  the  same  method. 

Some  authors,  particularly  Gowers,  do  not,  however,  believe  that  the 
knee-jerk  is  of  the  nature  of  a  simple  reflex,  but  explain  it  as  being  due 
to  a  contraction  of 'the  extensor  muscles  brought  about  by  direct 
mechanical  stimulation  while  the  muscle  is  in  a  hyperexcitable  condition 
as  a  result  of  a  reflex  increase  in  its  tonicity.  Cowers  believes  that  by 
putting  the  extensor  muscles  on  the  stretch  and  the  hamstring  muscles 
in  the  relaxed  condition,  afferent  impulses  are  transmitted  to  the  cord 
which  excite  the  efferent  neurons  of  the  extensor  muscles,  so  as  to  throAV 
them  into  a  hypertonic  condition,  during  which  the  tapping  of  the  ten- 
don directly  excites  a  contraction.  Of  course  this  hypothesis  would  ac- 
count once  and  for  all  for  the  remarkably  short  latency  of  the  knee- 
jerk,  but  on  the  other  hand  it  leaves  us  many  difficulties  to  explain ; 
such,  for  example,  as  the  fact  that,  although  tapping  the  tendon  produces 
the  jerk,  similar  tapping  of  the  muscle  itself  has  no  effect. 

The  effective  stimulus  of  the  jerk  is  a  slight  passive  increase  of  the 
tension  to  which  the  extensor  muscle  itself  is  subjected,  and  not  a  stimu- 
lation of  receptors  in  the  tendon,  for  it  still  occurs  after  the  tendon  has 
been  denervated.  The  importance  of  the  relationship  of  the  hamstring 
nerve  to  the  knee-jerk  becomes  evident  in  connection  with  reciprocal 
action;  thus,  when  the  flexor  is  contracted,  as  in  the  flexion  reflex,  the 
knee-jerk  disappears  (page  814),  whereas  when  the  hamstring  nerves  are 
cut,  it  is  augmented. 

Whatever  its  nature  may  be,  the  knee-jerk  is  of  value  because  of  the 
ease  with  which,  it  can  be  altered  not  only  by  conditions  affecting  the 
reflex  arc  concerned,  but  also  by  changes  occurring  elsewhere  in  the 
central  nervous  system.  The  best  known  of  these  conditions  is  that 
known  as  reinforcement.  This  is  brought  about  by  having  the  patient 
make  some  voluntary  muscular  effort  at  the  moment  that  the  tap  is  ap- 


830  THE    CENTRA!.    NERVOUS    SYSTEM 

plied  to  the  tendon.  If  this  voluntary  effort  coincides  in  time  with  the 
tapping  of  the  tendon,  the  knee-jerk  will  be  found  much  augmented;  but 
if  the  two  events  do  not  accurately  coincide,  we  may  find  instead  that 
the  knee-jerk  is  diminished;  that  is  to  say,  we  may  have  positive  fol- 
lowed by  negative  reinforcement.  The  most  usual  way  of  having  the 
patient  make  this  voluntary  effort  is  to  ask  him  to  lock  the  fingers  of  his 
two  hands  together  and  then  at  a  given  signal  try  to  pull  the  locked 
arms  apart. 

Similar  reinforcement  may  also  be  produced  by  the  application  of  a 
strong  sensory  stimulus  in  some  distant  part  of  the  nervous  system,  as, 
for  example,  by  pulling  the  hair  or  pinching  the  ear.  Accurate  work 
on  the  time  relationship  between  the  reinforcing  act  and  the  tap  on  the 
tendon  has  shown  that  the  knee-jerk  is  most  marked  when  the  tap  ac- 
curately corresponds  with  the  voluntary  effort  or  sensory  stimulation. 
It  then  quickly  declines  and  an  inhibitory  influence  appears  in  about 
0.3  to  0.6  of  a  second,  immediately  after  which  it  becomes  pronounced 
again,  gradually  fading  off  to  be  no  longer  evident  in  about  1.7  of  a 
second ;  that  is,  no  change  from  the  normal  will  be  found  in  the  knee-jerk 
in  about  1.5  of  a  second  after  the  reinforcing  act  (Lombard8). 

Many  explanations  have  been  offered  of  the  mechanism  involved  in 
this  reinforcement.  The  most  commonly  accepted  is  that  it  is  due-  to 
the  overflow  of  impulses  from  other  parts  of  the  nervous  system,  par- 
ticularly the  cerebrum,  upon  the  reflex  arc  concerned  in  the  knee-jerk. 
During  voluntary  effort  the  cerebral  impulses  discharged  down  the  spinal 
cord  pass  not  only  to  the  neuron  for  which  they  are  intended,  but  ir- 
radiate or  spread  to  other,  even  far  distant,  neurons,  thus  adding  their 
effect  to  that  of  the  afferent  impulse  entering  the  cord  locally.  The  suc- 
ceeding inhibition  may  be  assumed  to  be  due  to  successive  induction  (see 
page  824).  It  is  difficult  to  offer  direct  experimental  proof  in  support  of 
the  explanation,  but  indirect  evidence  is  furnished,  in  so  far  at  least  as 
the  augmentation  is  concerned,  by  the  results  of  the  experiments  which 
we  have  already  described  concerning  the  integration  of  allied  reflexes 
(page  822).  To  these  might  be  added  the  well-known  fact  that  the  simul- 
taneous application  of  two  subliminal  stimuli,  one  to  the  cerebral  cortex 
and  the  other  to  the  skin  of  the  corresponding  body  area,  may  call  forth 
a  contraction  of  certain  groups  of  muscles. 

AFFERENT  SPINAL  PATHWAYS 

The  nature  of  the  impulses  transmitted  by  the  various  afferent  path- 
ways in  the  spinal  cord.  We  have  seen  that  the  sensory  impulses  travel- 
ing from  the  periphery  to  the  spinal  cord  group  themselves  into  three 


TENDON    JERKS;   SENSOR'S    PATHWAYS    IN    BPINAL   CORD  831 

classes:  protopathic,  epicritic,  and  deep  or  muscular.  It  is  important 
now  for  us  to  consider  what  becomes  of  each  of  these  impulses  after 
entering  the  spinal  cord,  for  there  is  abundant  evidence  that  they  travel 
up  to  the  brain  by  different  pathways.  This  evidence  is  furnished  partly 
by  examination  of  the  cord  of  patients  who  during  life  exhibited  per- 
versions of  the  skin  sensations,  and  partly  by  producing  experimental 
lesions  affecting  different  parts  of  the  spinal  cord  in  animals.  In  the 
disease  syringomyelia,  for  example,  enlargement  of  the  central  canal 
of  the  spinal  cord  causes  rupture  of  certain  of  the  tracts  and  a  conse- 
quent disintegration  of  the  skin  sensations;  that  is,  the  sensations  of  pain 
and  temperature  disappear,  whereas  those  of  touch  and  deep  muscular 
sensation  remain.  Or,  from  the  experimental  side,  if  we  make  a  lateral 
hemisection  of  the  spinal  cord,  then  after  recovery,  so  far  as  we  can 
study  it  in  a  dumb  animal,  we  shall  be  able  to  show  that  certain  sen- 
sations have  disappeared,  whereas  others  remain.  It  is  evident,  how- 
ever, that  we  must  judge  by  objective  and  not  by  subjective  phenomena 
in  these  experiments,  and  our  results  are  only  approximate  and  very 
liable  to  misinterpretation.  Important  contributions  to  this  subject  have 
recently  been  made,  particularly  by  Holmes5  and  by  Collier,9  on  sol- 
diers wounded  in  the  spinal  cord. 

Summing  up  the  results  obtained  by  the  earlier  investigators,  Brown- 
Seqnard  some  sixty  years  ago  stated  that  hemisection  of  the  cord  on  one 
side  produced  the  following  results:  (1)  paralysis  of  voluntary  motion 
of  the  same  side;  (2)  paralysis  of  vasomotor  control  on  the  same  side, 
so  that  the  limb  is  hotter  than  normal;  (3)  anesthesia  for  all  kinds  of  sen- 
sation, except  muscular  sense  on  the  side  opposite  to  that  of  the  lesion ; 
(4)  a  condition  of  heightened  skin  sensitivity  (called  hyperesthesia)  on 
the  same  side  as  the  lesion,  with  the  exception  of  a  narrow  strip  of  skin 
corresponding  to  the  segment  at  which  the  cord  is  cut,  Avhich  is  anesthetic. 
These  results  indicate  that  in  general  the  skin  sensations  of  pain,  touch, 
and  temperature  cross  over  to  the  other  side  shortly  after  their  etatry 
into  the  cord,  but  that  the  deep  muscular  sensations  remain  in  large 
part  uncrossed.  More  recent  experimental  and  clinical  investigations 
do  not  support  Brown-Sequard's  conclusions. 

Ransom  has  recently  shoAvn  that  the  afferent  roots  of  the  spinal  cord 
contain  both  medullated  and  nonmedullated  nerve  fibers,  and  he  be- 
lieves that  the  former  transmit  the  epicritic  sensations,  and  the  latter 
the  protopathic.  By  tracing  those  different  kinds  of  fibers  into  the 
spinal  cord,  he  found  that  the  nonmedullated  lie  in  Lissauer's  tract  for 
one  or  two  segments  and  then  pass  into  the  substantia  gelatinosa  Ro- 
landi,  which,  therefore,  appears  to  be  the  nucleus  for  the  reception  of 
the  protopathic  impulses. 


832  THE    CENTRAL   NERVOUS   SYSTEM 

Among  the  reflex  activities  which  become  excited  by  these  nociceptive 
impulses  are  those  causing  a  rise  in  blood  pressure — pressor  impulses. 
This  correlation  between  nociceptive  impulses  and  those  affecting  the 
vascular  reflexes  has  prompted  Ranson  and  von  Hess10  to  make  a  care- 
ful study  in  cats  of  the  vascular  reflexes  that  could  be  elicited  from 
various  lesions  in  the  spinal  cord.  Two  kinds  of  vascular  reflexes  were 
studied,  pressor  and  depressor,  the  former  being  elicited  by  strong 
and  the  latter  by  very  feeble  stimulation  of  the  central  end  of  the 
sciatic  and  brachial  nerves.  They  found  that  the  pathways  for  pres- 
sor and  depressor  afferent  impulses  were  quite  different.  Thus,  after 
lateral  hemisection  of  the  cord,  the  depressor  reflex  obtained  by  weak 
stimulation  of  the  sciatic  on  the  same  side  as  the  lesion  was  normal, 
whereas  it  was  greatly  reduced  when  the  sciatic  nerve  on  the  opposite 
side  from  the  lesion  was  stimulated.  On  the  other  hand,  the  pressor 
reactions  that  were  most  markedly  diminished  were  those  from  the 
sciatic  on  the  same  side  as  the  lesion.  The  depressor  fibers  evidently 
cross  in  the  cord,  whereas  the  pressor  do  so  only  to  a  limited  degree. 
Further  it  was  found,  after  cutting  across  the  posterior  part  of  the 
cord,  that  the  pressor  reflexes  were  interfered  With  but  not  the  de- 
pressor, thus  indicating  that  the  former  are  transmitted  either  by  the 
posterior  columns  of  white  matter  or  by  the  gray  matter  of  the  posterior 
horns.  To  determine  which,  experiments  were  also  performed  in  which 
the  posterior  columns  were  alone  destroyed  and  the  results  compared 
with  others  in  which  the  tip  of  the  posterior  horn  was  included.  Since 
it  was  only  in  the  latter  experiment  that  any  interference  with  pressor  re- 
flexes was  found  to  occur,  it  was  concluded  that  the  posterior  horn  alone 
is  concerned  in  the  transmission  of  pressor  impulses. 

Regarding  conduction  of  the  afferent  impulses  which  in  consciousness 
produce  pain  and  of  those  concerned  in  the  reflex  changes  in  respiration, 
it  was  found  that  the  posterior  horn  of  gray  matter  is  not  concerned, 
from*  which  it  is  inferred  that  such  impulses  are  conducted  by  the  same 
afferent  path  that  is  involved  in  the  depressor  reflex;  that  is  to  say,  as 
we  have  indicated  above,  the  impulses  cross  in  the  cord  to  the  opposite 
side  and  ascend  in  the  lateral  funiculus.  The  pathway  of  the  epicritic 
and  pressor  sensations  in  the  cord  is  not  well  known.  It  is  believed, 
however,  that  impulses  of  touch  pass  up  the  posterior  column  on  the 
same  side  of  the  cord  for  four  or  five  segments,  and  then  gradually  pass 
to  the  anterior  column  of  the  opposite  side. 

But  for  obvious  reasons  it  is  mainly  from  clinical  observations  and 
accurate  postmortem  location  of  the  spinal  damage  that  the  problem 
must  finally  be  solved.  By  these  methods  it  has  been  shown  that  sen- 
sations of  pain  and  temperature  pass  through   the  opposite   lateral  col- 


TENDON    .IKKKS;    KKNSORY    I'A'I'I  I  \VA  VS    IN    SPINAL    CORD  833 

minis,  muscli  sense  through  the  homolateral  dorsal  column,  while  tactilt 
Si  nsations  pass  partly  by  the  uncrossed  fibers  of  the  dorsal  column  and 
partly  by  the  opposite  lateral  columns.  It  is  interesting  that  of  these 
two  paths  for  tactile  impulses  the  crossed  one  is  alone  closely  associated 
"with  the  tract  that  carries  pain   (Holmes). 

Bead  and  Thompson11  have  also  found  that  the  sensations  are  grouped 
to  the  extent  that  those  of  one  kind  travel  together,  whether  they  ars 
from  deep  or  superficial,  from  protopathic  or  epicritic  receptors.  When 
the  appreciation  of  cutaneous  pain  is  lost,  so  also  is  that  produced  by 
deep  pressure;  light  touch  and  heavy  touch  are  also  lost  simultane- 
ously. The  appreciation  of  all  degrees  of  temperature  is  abolished  at  the 
same  time.  The  ability  to  discriminate  between  two  points,  the  apprecia- 
tion of  "weight,  the  recognition  of  the  vibrations  of  a  heavy  tuning  fork 
applied  to  the  skin — all  depend  on  impulses  conducted  through  the 
homolateral  dorsal  columns. 

Because  the  crossing  in  the  cord  of  sensory  fibers  carrying  certain  sen- 
sations occurs  more  promptly  than  that  of  those  carrying  others,  and  for 
other  less  clearly  understood  reasons,  the  clinical  findings  are  often  difficult 
of  interpretation,  especially  when  the  lesions  are  only  partial.  The 
senses  of  pain  and  temperature  are  undoubtedly  lost  much  more  readily 
than  those  of  cutaneous  sensibility,  though  sometimes  the  reverse  con- 
ditions are  found.  If  a  partial  lesion  of  one-half  of  the  cord  occurs 
about  the  level  of  the  twelfth  dorsal  segment,  a  very  common  symptom 
is  loss  of  power  and  temperature  on  the  opposite  side,  but  not  of  touch 
even  when  strong  stimuli  are  applied.  This  crossed  relation  does  not, 
however,  occur  when  the  lesion  is  below  the  twelfth  dorsal. 

Regarding  the  number  of  segments  necessary  for  the  decussation  of 
each  kind  of  sense  fiber,  observations  on  cases  in  which  there  is  unilat- 
eral injury  of  the  cord  are  being  collected,  so  that  the  upper  limit  of  the 
anesthetic  area  may  be  compared  with  the  segmental  level  of  the  injury. 
It  appears  that  pain  and  thermal  impulses  cross  quickly  (i.  e.,  within  a 
segment  or  two)  in  the  middorsal  region,  but  that  those  of  touch  cross 
somewhat  more  gradually.  In  the  upper  segments  the  obliquity  of 
crossing  of  both  kinds  of  fibers  is  greater,  and  in  the  cervical  region 
it  may  require  five  or  six  segments  for  the  crossing  of  pain  impulses. 
With  this  increasing  obliquity,  a  distinction  appears  in  the  crossing  levels 
of  pain  and  temperature,  for  the  latter  cross  a  little  more  quickly. 
This  conforms  with  the  clinical  observation  that  thermal  appreciation 
may  be  disturbed  without  that  of  pain.  Even  the  thermal  impulses  do 
not  all  decussate  at  the  same  level,  for  anesthesia  to  heat  may  reach 
higher  up  on  the  skin  area  than  that  to  cold. 

When  recovery  occurs,  the  sensations  gradually  reappear  caudalwards. 


834  THE    CENTRAL    NERVOUS   SYSTEM 

Sometimes  in  high  lesions  of  the  cord  there  is  anesthesia  at  the  cor- 
responding level,  but  the  area  supplied  by  the  lower  spinal  roots,  espe- 
cially the  skin  in  the  region  of  the  anus,  is  sensitive  to  one  or  other 
kind  of  stimulation.  In  recovery,  too,  there  may  be  an  early  reap- 
pearance of  sensations  in  isolated  caudal  areas.  The  explanation  given 
for  these  results  is  that  the  fibers  carrying  different  kinds  of  sensation 
have  a  lamellar  arrangement  in  the  cord,  the  longest  fibers  being  on  the 
outside  (see  page  813).  When  a  partial  lesion  affects  the  mesial  fibers 
more  than  the  lateral,  there  will  accordingly  be  recovery  of  the  caudal 
skin  areas  before  those  higher  up. 


CHAPTER  XCIV 

EFFECTS  OF  EXPERIMENTAL    LESIONS  OF   VARIOUS   PARTS 

OF  THE  NERVOUS  SYSTEM 

Having  Learned  the  main  characteristics  of  reflex  net  ion,  we  shall  now 
proceed  to  study  the  peculiar  function  of  each  part  of  the  cerebrospinal 
system  by  noting  the  effects  which  follow  destruction  or  stimulation  of 
its  different  parts. 

THE  ANTERIOR  ROOT 

Section  of  an  anterior  root  produces  a  limited  degree  of  paralysis  in- 
volving several  muscles  having  no  functional  relationships  to  one  an- 
other. If  several  anterior  roots  are  cut,  the  paralysis  becomes  much 
more  extended,  and  is  followed  very  soon  by  an  evident  atrophy  of  the 
muscles  concerned.  Reflex  actions  from  these  muscles  are  of  course  im- 
possible. Stimulation  of  the  peripheral  end  of  a  cut  motor  root  causes 
partial  contraction  of  several  muscles,  no  definite  joint  movement,  how- 
ever, being  the  result,  because  the  affected  muscles  are  not  functionally  re- 
lated and  there  is  no  reciprocal  inhibition.  Flexor  and  extensor,  adductor 
and  abductor  may  contract  at  the  same  time,  thus  causing  the  joint  on  which 
they  act  to  become  muscle-bound.  It  is  in  the  plexus  that  the  nerve 
fibers  of  the  roots  become  sorted  out,  according  to  function,  into  motor 
and  sensory  nerve  trunks.  The  distribution  of  the  anterior  "root  fibers 
according  to  segments  in  man  for  the  cervical  and  lumbosacral  regions 
is  as  follows: 

C5  Deltoid,  biceps,  brachialis,  supinators,  rhomboids.  __  Occasionally 
radial  extensors.    Barely  pronator  radii  teres. 

C6  Pronators,  radial  extensors,  pectoralis  major  (clavicular  fibers), 
serratus  anticus. 

C7  Triceps,  extensor  carpi  ulnaris,  extensors  of  fingers,  rjectoralis 
major. 

C8       Flexors  of  wrist  and  fingers. 

Tl       Intrinsic  muscles  of  hand. 

S3,  4  Levator  ani,  sphincter  ani,  perineal  muscles. 

S2       Glutei,  biceps,  semitendinosus  and  semimembranosus. 

SI       Intrinsic  muscles  of  foot,  tibialis  posticus,  and  muscles  of  calf. 

L5       Muscles  of  ventrolateral  leg  (except  tibialis  anticus). 

L4       Extensors  of  leg  and  tibialis  anticus. 

835 


836  THE    CENTRAL    NERVOUS    SYSTEM 

The  knowledge  of  the  segmental  innervation  of  the  limb  muscles,  as 
furnished  in  the  above  table,  is  of  value  in  the  localization  of  spinal 
lesions.  Paralysis  of  the  extension  movements  of  the  wrist  and  fingers, 
along  with  the  triceps,  for  example,  usually  indicates  a  lesion  of  the 
seventh  cervical.  It  is  more  particularly  in  the  trunk,  however,  that 
the  segmental  innervation  of  the  muscles  is  evident.  The  innervation 
of  the  intercostal  muscles  being  unsegmental,  one  may  diagnose  the 
level  of  a  lesion  of  the  upper  thoracic  region  of  the  cord  by  observing  their 
behavior  during  deep  inspiration.  If  the  fingers  are  placed  in  the  in- 
tercostal spaces,  the  paralyzed  muscles  will  feel  limp  and  the  fingers 
sink  into  the  space  during  the  act. 

Localization  may  also  be  shown  by  studying  the  paralyses  of  the 
abdominal  muscles  when  the  lesion  involves  one  of  the  lower  six  thoracic 
segments.  When  the  patient  with  a  lesion  of  the  eleventh  thoracic  raises 
his  head  from  the  bed  or  coughs,  the  rectus  contracts,  but  the  iliac  re- 
gions bulge  owing  to  paralysis  of  the  lower  portions  of  the  obliques.  Under 
the  same  conditions,  when  the  ninth  segment  is  involved  the  rectus  contracts 
from  about  one  inch  above  the  umbilicus,  whereas  below  this  level  it  remains 
uncontracted,  so  that  the  umbilicus  is  pulled  up. 

Besides  muscular  movement,  stimulation  of  the  anterior  roots  in  lightly 
anesthetized  animals  sometimes  causes  evidence  of  general  reflex  re- 
sponse and  of  pain.  The  explanation  is  that  there  are  present  in  the  an- 
terior root  certain  sensory  fibers  which  are  derived  from  the  posterior  root 
but  recur  in  the  anterior,  so  as  to  reach  the  membranes  of  the  spinal 
cord  where  they  terminate.  The  stimulation  of  the  peripheral  end  of  the 
motor  root  must  produce,  therefore,  the  same  reflex  responses  as  stimu- 
lation of  the  central  end  of  the  sensory  root.  Stimulation  of  the  cen- 
tral end  of  a  motor  root  has  of  course  no  effect. 


THE  POSTERIOR  ROOT 

The  posterior  root  is  the  patlrway  by  which  impulses  of  the  various 
receptors  enter  the  spinal  cord.  Section  of  any  considerable  number  of 
posterior  roots  causes  therefore,  anesthesia  of  the  corresponding  skin 
and  muscle  areas,  but  such  a  result  does  not  become  evident  when  one 
root  alone  is  cut,  because  the  sensory  area  supplied  by  each  root  over- 
laps at  least  half  of  that  supplied  by  the  neighboring  roots.  Although 
it  is  often  difficult  to  distinguish  the  segmental  distribution  in  the 
ramification  of  the  fibers  of  the  motor  roots  by  finding  what  muscles 
they  influence,  this  is  more  evident  in  the  case  of  the  sensory  roots.  On 
the  trunk  itself  this  segmental  arrangement  is  very  plain,  but  in  the 


EFFECTS   OF    EXPERIMENTAL    LESIONS 


837 


extremities  it  is  riol  a1  first  sighl  bo  clear,  although  it  can  be  accurately 
worked  out,  as  is  indicated  in  the  accompanying  diagram  (Fig.  21S). 

In  attempting  to  determine  the  level  of  a  lesion  from  the  sensory  paraly- 
sis, some  confusion  often  arises  on  accounl  of  the  oblique  course  of  the 
decussation  of  the  sensory  fibers  in  the  spinal  cord,  fibers  for  the  differenl 
sensations  not  crossing  at  the  same  levels.  For  example,  the  appreciation 
of  moderate  temperature  is  often  lost  slightly  higher  than  that  of  pain. 
The  appreciation   of  the   vibrations  caused  by  drawing  the  base  of  a 


Fig.    218. — Diagram    showing    the    segmental    arrangement    of    the    sensory    nerves.       (From    Turves 

Stewart.) 

heavy  tuning  fork  over  the  skin  is  often  very  useful  in  locating  the 
lesion,  particularly  in  the  abdomen.  "When  this  method  is  used  on  the 
thorax,  however,  the  skin  should  be  pulled  up  in  folds  before  the  fork 
is  applied,  since  otherwise  the  thorax  will  act  as  a  resonator  and  spread 
the  sensation.  Section  of  two  or  more  sensory  roots  produces  a  very 
definite  area  of  anesthesia,  involving  all  the  skin  sensations  as  well  as 
several  of  those  of  deep  sensation. 

If  the  severed  roots  include  all  of  those  going  to  one  of  the  extremities, 
there  is  not  only  an  entire  absence  of  sensation,  but  a  marked  interference 


838  THE    CENTRAL   NERVOUS    SYSTEM 

with  the  usefulness  of  the  limb,  the  condition  being  called  apesthesia. 
The  exact  results  depend  somewhat  on  the  type  of  animal.  If  all  the 
posterior  roots  of  the  anterior  extremity  are  cut  in  a  monkey,  the 
corresponding  limb  will  not  be  used  in  climbing  or  for  other  purposes. 
It  will  appear  to  he  completely  paralyzed,  unless  when  the  opposite 
normal  limb  is  in  vigorous  activity,  when  the  apesthetic  arm  may  be 
moved   in   association. 

On  careful  examination,  however,  it  will  be  found  that  marked  dif- 
ferences exist  in  the  types  of  paralysis  produced  by  the  section  of  the 
anterior  and  the  posterior  roots.  When  a  motor  root  is  cut  no  reflexes 
are  possible  either  from  the  skin  or  from  the  cerebral  cortex,  and  the 
muscles  undergo  atrophy.  After  section  of  the  posterior  root,  on  the 
other  hand,  although  reflexes  from  the  skin  area  affected  are  impos- 
sible, yet  movements  may  be  elicited  by  artificial  stimulation  of  the 
cerebral  cortex,  and  the  muscles  do  not  atrophy  to  the  same  extent. 

If  only  one  sensory  root  of  an  extremity  is  left  uncut — for  example, 
the  last  cervical — so  that  the  skin  of  the  hand  is  still  supplied  with 
sensation  but  all  the  deep  receptors  are  severed,  then  the  limb  may  be 
used  to  a  modified  degree.  It  may  be  used  by  the  monkey  to  pick  up 
nuts,  but  the  movement  will  be  distinctly  clumsy  and  ataxic  in  nature. 
Instead  of  neatly  picking  up  the  nuts,  he  will  make  wild  movements 
and  often  miss  them. 

The  apesthesia  is  not  so  profound  in  lower  animals.  After  section  of 
all  the  sensory  roots  to  both  hind  limbs  in  the  dog,  there  may  be  a 
certain  attempt  at  walking  on  the  part  of  the  affected  limb;  that  is  to 
sa3T,  when  the  animal  tries  to  progress,  the  hind  limbs,  although  at  first, 
merely  dragged  along  the  "round,  afterwards  begin  to  execute  walking 
movements,  which  however  are  xery  jerky  or  ataxic  in  nature  and  con- 
tribute little  to  the  forward  progression  of  the  animal,  although  he 
may  succeed  to  a  certain  extent  in  supporting  the  body  by  the  hind  limbs. 
The  importance  of  the  sensory  root  in  controlling  the  contraction  of 
the  muscles  is  further  illustrated  by  comparing  the  contraction  curve  of 
a  muscle  produced  by  stimulating  its  uncut  motor  nerve  with  that  pro- 
duced by  stimulating  the  peripheral  end  of  the  cut  nerve.  In  the  former 
case,  the  curve  is  more  prolonged  and  shows  a  gradual  relaxation, 
whereas  when  the  peripheral  end  of  the  cut  nerve  is  stimulated,  the  con- 
traction is  brief  and  the  relaxation  is  followed  by  a  distinct  rebound 
or  "inertia  swing,"  as  it  is  called.  That  this  difference  depends  on 
afferent  impulses  is  indicated  by  the  fact  that,  after  section  of  the 
posterior  roots,  stimulation  of  the  uncut  nerve  in  the  limb  will  produce 
the  same  effect  as  occurs  when  the  cut  nerve  is  stimulated.  These  re- 
sults can  be  very  clearly  obtained  in  the  case   of  the  frog,  in  which 


EFFECTS   OF    EXPERIMENTAL   LESIONS  839 

also  it  will  he  noted  Mini  after  section  of  the  posterior  roots  of  one  side, 
the  corresponding  limb  hangs  Lower  than  its  fellow  because  its  muscles 
are  toneless. 

Stimulation  of  the  central  end  of  a  cut  afferent  root  produces,  as  lias 
already  been  indicated,  a  contraction  of  the  muscles  accompanied  by  a 
reciprocal  inhibition  of  their  antagonists,  so  that  sonic  definite  move- 
ment of  the  joint  takes  place.  This  movement  is,  however,  merely  a 
flexion  or  extension  or  rotation,  but  with  no  very  evident  object  in  view. 
In  this  regard  it  is  quite  different  from  the  purposeful  movement  which 
results  from  stimulation  of  a  skin  area,  indicating,  therefore,  that  the 
receptor  apparatus  itself  must  contribute  to  the  nerve  impulse  some- 
thing which  causes  it  to  bring  about  a  more  perfectly  integrated  move- 
ment of  the  musculature  than  is  the  case  when  the  nerve  trunk  is  di- 
rectly stimulated. 

Besides  the  movements  of  the  musculature  innervated,  from  segments 
which  are  beside  those  of  the  stimulated,  afferent  root,  there  is  a  general 
reflex  response  through  other  centers,  for  example,  the  respiratory  and 
the  vasomotor;  and,  in  animals  which  are  not  deeply  anesthetized,  there 
is  also  evidence  of  pain.  Stimulation  of  the  peripheral  end  of  the  sen- 
sory root  has  of  course  no  effect, 

THE  SPINAL  CORD  AND  BRAIN  STEM 

The  results  of  transsection  of  the  cord  have  been  already  sufficiently  de- 
scribed. It  remains  to  discuss  the  effect  of  total  ablation  or  removal  of 
portions  of  the  cord.  As  would  be  expected,  there  is  a  marked  degree 
of  shock  for  some  weeks  after  ablation.  During  this  shock  the  tone 
of  the  sphincters  and  vessels  is  greatly  depressed,  so  that  congestion 
and  edema  of  the  feet,  diarrhea  and  retentio  urinae  are  marked,  and 
ulceration  of  the  skin  is  practically  unavoidable.  After  a  few  weeks, 
however,  recovery  becomes  evident  in  so  far  as  the  blood  vessels  and 
sphincters  are  concerned,  but  the  skeletal  musculature  atrophies  very 
extensively  and  comes  to  resemble  connective  tissue.  If  the  spinal 
ablation  involves  the  thoracic  region,  for  example,  the  affected  in- 
tercostal muscles  become  stiff  and  parchment-like;  the  bones  also  get 
brittle,  and  visible  perspiration  can  not  be  produced.  On  the  other 
hand,  after  some  time  the  sphincters  functionate  more  or  less  normally, 
the  hair  is  shed  and  renewed  in  normal  fashion,  and  the  application  of 
cold  to  the  skin  causes  the  usual  vascular  reaction.  It  is  of  interest 
that  in  female  animals  whose  lumbar  spinal  cord  has  been  removed, 
pregnancy  may  take  place  normally,  followed  by  lactation. 

Section  Just  Above  the  Medulla. — After  such  an  operation,  the  ani- 


S40  THE    CENTRAL    NERVOUS    SYSTEM 

mal — -"bulbospinal,  as  it  is  called — shows  a  greater  integration  of  re- 
flexes than  is  possible  -when  the  section  is  between  the  medulla  and  the 
spinal  cord.  Its  reflex  responses  are  more  broadly  integrated,  but  the 
extremities  are  incapable  of  executing  movements  that  are  of  any  value 
in  progression.  Movements  like  those  of  progression  may  occur,  but  they 
are  quite  ineffective.  Such  animals  show  marked  superiority  over  strictly 
spinal  ones  on  account  of  the  fact  that  in  the  medulla  are  located  so 
many  of  the  important  centers  which  control  circulation,  respiration 
and  the  anterior  openings  of  the  body;  that  is,  the  mechanisms  which 
accompany  the  first  stages  in  the  digestion  of  food. 

Section  Just  Behind  the  Posterior  Corpora  Quadrigemina. — A  very 
distinct  improvement  becomes  noticeable  in  the  responses  of  the  animal. 
This  condition  has  been  studied  most  carefully  in  the  case  of  the  frog, 
which  after  such  a  section  can  walk,  spring  and  swim  apparently  like  a 
normal  animal,  and  croaks  when  the  side  of  the  body  is  stroked.  In 
the  mammal  a  similar  increase  in  the  complexity  of  movement  is  evident, 
but  there  is  not  yet  any  power  of  progression. 

Section  in  Front  of  the  Anterior  Corpora  Quadrigemina. — When  the 
medulla,  pons  and  mesencephalon  are  present,  as  well  as  the  spinal  cord, 
the  condition  known  as  decerebrate  rigidity  supervenes.  This  is  most 
marked  in  mammals,  but  is  also  present  to  a  certain  extent  in  much 
lower  animals,  as,  for  example,  in  frogs.  It  consists  of  a  tonic  condition 
of  the  postural  musculature  of  the  body,  mainly  of  the  extensor  mus- 
cles; the  elbows  and  knees  are  extended  and  they  resist  passive  flexing; 
the  tail  is  stiff  and  straight:  the  neck  and  head  are  retracted.  The  con- 
dition is  undoubtedly  due  to  overactivity  of  the  reflex  tonic  function  of 
the  spinal  centers,  for  it  disappears  when  the  posterior  spinal  roots  are 
cut.  The  reflexes  that  depend  on  the  tone  of  the  musculature — for  example, 
the  knee-jerk  and  extensor  thrust — are  very  pronounced  in  such  an  ani- 
mal, and,  on  account  of  the  higher  integration  present,  reflexes  appear 
that  are  absent  in  animals  having  the  cerebrospinal  axis  cut  lower  down. 
For  example,  although  such  an  animal  can  not  feel,  yet  when  a  stimulus 
is  applied  that  in  a  normal  animal  would  cause  pain,  the  vocal  apparatus 
may  be  excited  so  that  a*  sound  or  cry  of  pain  is  produced.  The  rigidity 
does  not  affect  the  respiratory  muscles.  After  such  an  operation,  how- 
ever, normal  respiration  is  much  more  likely  to  be  maintained  if  the 
section  is  in  front  of  the  anterior  corpora  quadrigemina  than  behind  it. 

Removal  of  the  Cerebral  Hemispheres. — This  furnishes  us  with  what 
is  known  as  a  decerebrate  preparation — that  is,  one  in  which  the  animal 
retains  everything  from  the  basal  ganglia  downward.  The  operation 
produces  a  condition  which  varies  according  to  the  habits  of  the  animal. 
Thus,  in  such  fish  as  the  Elasmobranchs,  which  depend  for  their  impressions 


EFFECTS   OF    EXPERIMENTAL    LESIONS  841 

very  largely  on  the  sense  of  smell,  wc  find  that  decerebration  causes  the  ani- 
mal to  become  completely  immobile.  It  can  not  seek  food  because  the 
sense  of  smell,  upon  which  it  ordinarily  solely  depends,  has  been  de- 
stroyed. In  a  bony  fish,  on  the  other  hand,  decerebration  causes  very 
little  difference  in  the  behavior  of  the  animal,  provided  the  thalami 
and  optic  lobes  have  been  left  intact.  It  continually  swims  about  and  is 
able  to  distinguish  edible  from  nonedible  material. 

In  the  frog  the  result  depends  very  largely  upon  whether  the  optic 
thalami  have  been  simultaneously  removed.  Even  Avhen  these  structures 
have  been  removed  along  with  the  cerebrum,  the  animal  at  first  appears 
very  little  different  from  the  normal  frog.  It  springs  away  when  touched, 
it  climbs  up  an  inclined  plane,  and  when  thrown  in  water  it  swims.  It 
is,  however,  quite  incapable  of  producing  any  spontaneous  movement, 
and  is  in  short  nothing  more  than  an  extremely  complex  machine,  re- 
acting always  in  exactly  the  same  way  to  the  same  kind  of  stimulus. 
When  the  optic  thalami  are  also  intact,  spontaneous  movements  are  said 
to  be  occasionally  observed.  Such  a  frog  is  said  indeed  to  react  on  the 
approach  of  winter  as  normal  frogs  do  by  preparing  itself  for  hiberna- 
tion, and  with  spring,  to  resume  its  activity  and  feed  itself  by  catching 
insects. 

In  the  bird,  in  wThich  the  operation  of  removing  the  cerebral  hemi- 
spheres is  a  very  easy  one,  the  movements  after  decerebration  may  be 
quite  complicated,  particularly  if  the  optic  lobes  are  intact.  Such  a 
bird  is  more  active  than  usual  during  daylight,  but  becomes  perfectly 
still  in  the  dark.  It  is,  however,  unable  to  distinguish  friends  from  ene- 
mies, and  it  showTs  no  fear. 

As  we  ascend  further  in  the  animal  scale,  the  operation  of  decere- 
bration becomes  very  difficult.  Goltz,  however,  succeeded  some  years 
ago  in  removing  practically  all  of  the  cerebrum  from  a  dog  by  perform- 
ing the  operation  in  three  stages  separated  by  considerable  intervals  -of 
time.  The  animal  lived  eighteen  months  after  the  last  operation,  and 
during  this  time  it  behaved  exactly  like  an  automatic  machine.  All  its 
reflexes  were  perfectly  normal.  It  could  not  distinguish  objects,  but  a 
bright  light  caused  it  to  close  its  eyes.  During  daytime  it  walked  con- 
tinuously up  and  down  its  cage,  whereas  at  night  it  would  sleep  and 
remain  perfectly  quiet.  When  food  was  placed  in  the  mouth,  the  dog 
would  masticate  and  swallow  in  a  perfectly  normal  fashion,  and  would 
reject  unpalatable  food.  While  asleep,  a  very  loud  sound  might  awaken  it, 
and  when  a  harmful  stimulus  was  applied  to  the  skin,  the  animal  would 
snarl  and  growl  and  attempt  to  fight  the  offending  object.  There  were 
absolutely  no  signs  of  pleasure  or  of  recognition  of  the  person  that  fed 
it  or  of  fear. 


842  THE    CENTRAL    NERV01   -    SYSTEM 

Prom  these  results  it  is  in  general  clear  that  the  brain  stem  is  ahle 
to  adjust  the  motor  and  the  visceral  reactions  of  the  animal  to  changes 
in  the  immediate  environment,  but  that  no  power  of  spontaneous  move- 
ment is  possible.  Although  in  the  higher  apes  and  in  man  removal  of 
any  considerable  part  of  the  cerebral  cortex  is  impossible,  yet  we  may 
infer,  from  the  results  "which  have  just  been  considered,  that  in  the 
higher  animals  more  and  more  of  the  action  becomes  shifted  to  the 
motor  centers  of  the  cerebrum.  Reflexes  which"  in  the  lower  animals 
involve  only  a  spinal  or  a  bulbo-spinal  tract,  also  involve  in  the  higher 
forms  a  cerebral  path  which  is  laid  down  only  as  the  result  of  experience 
and  education.  The  newly  born  infant  is  able  to  perform  fewer  move- 
ments than  is  the  case  in  the  lower  forms  of  animal  life,  but  his  power 
of  learning  new  moA'ements  is  incomparably  greater.  He  inherits  less 
in  the  way  of  stereotyped  reflexes,  but  in  place  of  these  he  possesses 
innumerable  nerve  tracts  leading  through  cerebral  neurons,  through 
which  new  reflex  responses  may  be  laid  down  as  a  result  of  education. 

In  connection  with  these  experiments  it  is  interesting  to  note  that 
in  lower  animals  it  can  readily  be  demonstrated  that  the  general  in- 
fluence of  the  higher  on  the  spinal  centers  is  of  an  inhibitory  nature. 
Thus,  the  latent  time  of  the  flexion  reflex  in  the  decerebrate  frog,  as 
judged  by  the  Turck  method,*  is  very  much  prolonged  when  a  stimulus, 
such  as  that  produced  by  a  crystal  of  common  salt,  is  applied  to  the 
optic  lobes  just  posterior  to  the  cerebrum.  In  general,  the  influence 
which  the  cerebrum  exercises  on  the  spinal  centers  is  an  inhibitory  one, 
whereas  that  of  the  cerebellum  is  augmentatory. 


*Turck's  method  consists   in  measuring  with  a  metronome   the  time  that   elapses  between   dipping 
the  foot  into  weak  acid  solution  and  the  reflex  flexion  of  the  leg. 


.  CHAPTEE  XCV 
CEREBRAL  LOCALIZATION 

Of  much  greater  practical  importance  than  the  experiments  in  which 
the  entire  cerebrum  is  removed,  as  described  in  the  last  chapter,  are 
those  in  which  various  parts  of  it  are  destroyed  or  stimulated.  From 
the  results  conclusions  may  be  drawn  regarding  the  important  subject 
of  cerebral  localization.  The  effects  produced  by  removal  or  stimulation  of 
different  parts  of  the  cerebral  cortex  vary  considerably,  some  parts  of  the 
cortex  being  set  apart  for  the  control  of  the  motor  mechanism  of  the 
body,  others  for  the  reception  and  interpretation  of  afferent  stimuli, 
while  others,  and  these  by  far  the  most  extensive,  are  concerned  in  the 
correlation  or  association  of  the  sensory  and  motor  centers.  It  may 
be  stated  in  general  that:  (1)  The  precentral  region  of  the  cerebrum 
contains  the  centers  of  higher  thought,  (2)  The  ascending  frontal  con- 
volution immediately  in  front  of  the  precentral  sulcus  contains  the 
chief  motor  centers,  a  center  being  distinguishable  for  each  muscular 
grouping  of  the  body.  (3)  The  postcentral  convolution  has  to  do  with 
the  centers  for  the  immediate  reception  of  sensory  stimuli,  the  so-called 
sensory  centers.  (4)  A  large  area  occupying  most  of  the  parietal  lobe 
and  part  of  the  occipital  is  undoubtedly  associational  in  its  function, 
since  from  it  no  response  can  be  obtained  by  stimulation,  etc.  (5)  Be- 
hind this,  in  the  occipital  lobe,  there  is  a  center  having  to  do  with  the 
reception  of  visual  impulses.  (6)  In  the  upper  convolution  of  the  tem- 
poro-sphenoidal  lobe,  is  a  similar  center  for  hearing. 

These  centers  have  been  differentiated  from  one  another  by  anatomical, 
experimental  and  clinical  research.  At  present  we  shall  confine  ourselves 
to  the  experimental  results.  These  are  obtained  by  ablation  and  stimula- 
tion, and  in  considering  the  results  it  will  be  convenient  to  divide  the 
centers  into  motor,  sensory,  and  nonreactive. 

ABLATION  OF  THE  MOTOR  CENTERS 

Removal  of  the  cortex  from  the  area  which  controls  the  movements  of 
a  definite  part  of  the  body— say,  the  arm — will  be  found  to  produce  an 
immediate  and  profound  muscular  paralysis.  The  animal  does  not  use 
the  paralyzed  extremity  for  any  purpose  whatsoever,  and  yet  the  mus- 

843 


844  THE    CENTRAL   NERVOUS   SYSTEM 

cles  do  not  undergo  any  more  atrophy  than  can  be  accounted  for  by 
disuse.  The  extremity  does  not  suffer  from  any  of  the  nutritional  dis- 
turbances which  Ave  saAv  supervene  upon  destruction  of  the  motor  cen- 
ter in  the  cord;  and  likewise  local  reflex  actions  elicited  by  stimulation 
of  the  local  receptors  are  perfectly  normal.  A  pinprick,  for  instance, 
causes  the  usual  flexion  reflex. 

After  some  weeks  the  limb  begins  to  recover  and  can  be  used  in 
volitional  movement.  Recovery  rapidly  progresses  until,  in  the  case  of 
the  higher  apes,  it  becomes  almost  complete  in  a  little  over  four  months. 
It  occurs  earlier  in  the  lower  animals.  When  a  center  is  destroyed  on 
the  cerebral  cortex  in  the  case  of  man,  only  partial  recovery  takes  place. 
So  that  in  general  we  may  say  that  the  higher  the  animal  in  the  animal 
scale,  the  less  complete  will  be  recovery  from  the  paralysis  produced  by 
cerebral  ablation. 

Regarding  the  nature  of  the  recovery,  several  possibilities  exist:  either 
the  nerve  centers  become  regenerated  in  the  destroyed  area,  or  the  cor- 
responding area  of  the  opposite  hemisphere  or  some  other  part  of  the  same 
hemisphere  or  the  basal  ganglia  assume  the  function.  Evidence  has  been 
furnished  by  Sherrington  and  Graham  Brown12  tending  to  show  that 
the  last  of  these  is  the  most  likely  cause  for  the  recovery.  Thus,  it  was 
found,  in  working  on  the  arm  centers  on  the  brain  of  the  chimpanzee, 
that  after  complete  recovery  of  the  paralysis  produced  by  removal  of 
the  center  on  one  side,  stimulation  of  the  area  that  had  been  removed 
caused  no  movements,  indicating  that  no  regeneration  had  occurred,  and 
that  removal  of  the  corresponding  center  of  the  opposite  hemisphere, 
although  followed  by  paralysis  of  the  arm  to  which  it  corresponded,  still 
did  not  cause  any  paralysis  of  the  limb  which  had  recovered  from  the 
previous  operation.  To  see  whether  some  other  part  of  the  gray  cortex 
might  haA*e  assumed  the  lost  function,  the  postcentral  convolution  was 
removed  two  months  after  the  removal  of  the  arm  centers.  Although 
a  temporary  weakness  of  both  arms  resulted,  the  voluntary  movements 
were  soon  as  good  as  before.  These  results  are  of  course  exactly  what 
Ave  should  expect  from  the  experiment  on  the  dog,  already  described 
in  which  the  cerebral  cortex  had  been  entirely  removed,  and  the  conclusion 
that  Ave  must  draAV  is  that  the  basal  ganglia  assume  the  function  of  the 
lost  cerebral  cortex. 

STIMULATION  OF  THE  MOTOR  CENTERS 

To  investigate  the  effects  of  stimulation,  it  is  found  that  the  stimulus  is 
best  applied  by  the  electrical  method,  one  pointed  electrode,  called  the  stim- 
ulating, being  applied  to  the  area  under  investigation,  and  the  other, 


CEREBRAL   LOCALIZATION  .  845 

called  the  indifferent  electrode  and  consisting  of  a  flat  plate,  being 
placed  on  some  other  part  of  thebody,  such  as  the  skin  of  the  back.  This 
unipolar  method  gives  much  finer  results  than  when  the  ordinary  bipolar 
electrodes  are  employed. 

Before  we  describe  the  results  "which  have  been  obtained  by  the  use 
of  this  method,  a  question  arises  which  it  may  be  well  to  consider 
briefly ;  namely,  how  do  we  know  that  the  electric  current  is  really  stimu- 
lating the  center  present  in  the  gray  matter  of  the  cortex,  and  not 
the  numerous  nerve  fibers  that  constitute  the  white  matter  of  the  brain 
and  along  which,  between  the  two  electrodes,  it  is  plain  some  of  the 
electric  current  must  pass?  The  evidence  that  we  are  really  stimulating 
centers  is  as  follows:  (1)  The  latent  period  for  a  response  produced  by 
stimulating  the  centers  is  much  longer  than  that  which  follows  upon  di- 
rect stimulation  of  the  white  matter.  (2)  Under  deep  narcosis,  as  that 
produced  by  chloral  or  morphine,  the  effect  of  stimulation  of  the  gray 
mailer  is  greatly  delayed  and  altered  in  type;  whereas  stimulation  of  the 
white  matter  gives  the  usual  response.  (3)  A  weaker  current  suffices  to 
stimulate  the  gray  matter  than  that  required  for  the  exposed  white 
matter. 

In  order  to  demonstrate  the  movements  which  follow  stimulation  of 
the  cerebral  cortex,  it  is  necessary',  as  will  be  inferred  from  the  pre- 
ceding remarks,  that  the  animal  be  not  too  deeply  anesthetized.  Fur- 
thermore, it  is  necessary  to  be  very  careful  in  adjusting  the  strength 
of  stimulation  employed,  for  the  results  vary  considerably  accordingly. 
"When  the  stimulus  is  of  the  proper  intensity,  the  movements  are  located 
in  some  particular  group  of  muscles, — 'for  example,  those  of  the  thumb 
or  of  the  hand, — whereas,  if  the  stimulation  is  strong,  the  movements 
spread  over  much  larger  areas.  As  a  result  of  feeble  or  moderate  stimu- 
lation, it  is  found  that  the  muscles  which  move  are  those  of  the  opposite 
side  of  the  body,  and  that  the  localization  is  finer  the  higher  the  position 
of  the  animal  in  the  scale  of  development.  The  movements  are  perfectly 
coordinate  and  purposeful  in  character,  and  reciprocal  innervation  is 
evident. 

There  is,  however,  a  marked  difference  in  the  reactions  obtained  by 
stimulation  of  the  motor  cortex  and  those  obtained  by  eliciting  spinal 
reflexes.  For  example,  the  movements  produced  by  stimulation  of  the 
cortex  are  much  more  readily  modified  by  slight  variations  in  the  con- 
dition of  the  animal,  the  blood  supply,  the  degree  of  narcosis,  etc.,  than 
are  those  elicited  by  stimulation  of  receptor  neurons.  A  careful  study 
of  this  difference  has  been  made  in  recent  years  by  Brown  and  Sher- 
rington.13 They  observed  the  behavior  of  two  antagonistic  muscles 
acting  on  the  elbow  when  the  respective  cortical  centers  were  stimu- 


846  THE    CENTRAL   NERVOUS    SYSTEM 

lated,  and  found  that  the  latent  periods  were  very  variable,  the  after- 
effects indefinite,  and  inhibition  more  prominent  than  excitation.  More- 
over, the  inhibition  was  more  or  less  independent  of  the  simultaneous 
excitation  of  the  antagonistic  muscle,  in  which  respect  it  therefore  dif- 
fered from  the  type  exhibited  in  the  reciprocal  innervation  of  the  spinal 
reflexes  (see  page  814).  Nor  were  the  results  obtained  from  a  given 
cortical  center  always  the  same;  thus,  if  a  point  giving  a  certain  re- 
sponse was  stimulated  immediately  after  previous  stimulation,  the  re- 
sult was  often  reversed;  if  it  was  inhibition  in  the  first  instance,  it 
might  be  excitation  immediately  afterward.  But  if  sufficient  time  was 
allowed,  then  the  response  was  always  of  the-  same  kind. 

By  comparing  the  effect  of  simultaneous  stimulation  of  an  afferent 
spinal  root  and  of  a  flexion  or  extension  point  on  the  cortex,  it  was 
found  that  the  stimulation  of  the  afferent  root  when  a  flexion  point 
Mas  being  stimulated  augmented  the  flexion,  but  when  an  extension 
point  was  stimulated,  stimulation  of  the  afferent  root  might  change  the 
response  to  flexion,  the  exact  result  depending  considerably  on  the  rel- 
ative strength  of  the  two  stimuli.  The  general  conclusion  that  may  be 
drawn  from  these  results  is  that  the  special  function  of  the  cortex  is  to 
reverse  the  centers  of  purely  spinal  reflexes  when  such  reversal  is  de- 
sirable or  necessary.  The  cortex  dominates  the  spinal  reflexes,  and  in 
general  it  may  be  said  that  its  main  effect  is  inhibitory  in  nature. 

It  is  particularly  by  the  use  of  the  method  of  moderate  electrical  stimu- 
lation that  exact  localization  has  been  worked  out  on  the  cerebral  cor- 
tex. As  would  be  expected,  this  localization  is  much  less  defined  and 
definite  in  the  lower  as  compared  with  the  higher  animals.  In  the 
higher  apes,  it  has  been  found  that  the  motor  centers  are  limited  to  a 
narrow  strip  of  cortex  immediately  in  front  of  the  Rolandic  fissure — 
the  precentral  area,  as  it  is  called.     (Fig.  219.) 

From  the  accompanying  figure,  it  will  be  noted  that  the  centers  are 
arranged  from  below  upward,  in  the  reverse  order  to  that  in  which  the 
muscular  groups  occur  in  the  body;  that  is  to  say,  the  face,  neck,  etc., 
are  located  lowest  on  the  cortex,  and  the  leg  highest  up.  It  will  further 
be  noted  that  the  extent  of  the  centers  for  the  neck  and  tongue  is  very 
much  greater  than  for  the  body  or  leg,  that  for  the  arm  being  interme- 
diate. It  is  not,  therefore,  the  extent  of  the  muscular  tissue  that  de- 
termines the  size  of  the  cortical  area  controlling  its  movements,  but 
the  type  or  complexity  of  the  movements  that  the  muscles  perform. 
The  complex  movements  of  the  tongue  and  the  vocal  cords  evidently 
require  greater  cortical  representation  than  do  the  coarser  movements 
of  the  large  mass  of  muscular  tissue  of  the  trunk.  The  centers  extend 
somewhat  upon  the  mesial  aspect  of  the  brain,  but  occupy  here  only  a 


CKRLBRAL    LOCALIZATION 


847 


very  small  part  of  the  superficial  gray  matter.  They  extend  also  into 
the  fissure  of  Rolando  and  the  other  fissures,  and  the  extent  of  the  ex- 
citable area  which  is  thus  buried  away  in  the  fissures  may  exceed  that 
on  the  free  surface  of  the  hemispheres. 

It  will  be  noted  that  there  are  two  centers  for  the  movements  of  the 
eyes,  one  in  the  frontal  lobe  isolated  from  the  motor  area,  and  the 
other  at  the  tip  of  the  occipital  lobe.  The  former  is  the  motor  center 
for  the  conjugated  movements  of  the  two  eyeballs,  whereas  the  latter 
functionates  in  association  with  the  so-called  visual  center,  which  re- 
ceives the  visual  impressions  and  transmits  them  to  other  parts  of  the 


Anus  &  Vagina 
Toes// 
Ankle 
Knee 


,Sulcus  centralis 


.Abdomen 
Chest 


Shoulder 


'AEVE5 


Fingers 
&  thumb. 


Closure 
of  jaw 


Opening 
of  jaw 

Vocal  cords 


Sulcus  centralis 


Mastication 


Fig  219. — Outer  aspect  of  the  brain  of  the  chimpanzee,  showing  the  position  of  the  centers. 
Electric  stimulation  at  the  parts  indicated  causes  coordinate  movements  of  the  corresponding  mus- 
cle  groups.      (After   Sherrington.) 

brain  to  be  interpreted  and  correlated.  Excitation  of  the  center  for 
eye  movements  in  the  frontal  lobe,  say,  of  the  right  side,  causes  con- 
jugate deviation  of  both  eyes  to  the  opposite  side,  that  is,  to  the  left; 
and  it  can  readily  be  shown  that  this  movement  of  the  eyeballs  is  the 
result  of  reciprocal  innervation  of  the  extraocular  muscles  (page  814). 
Even  at  the  risk  of  repetition  we  will  again  describe  the  fundamental 
experiment  that  demonstrates  this.  When  the  eyes,  as  in  the  above 
experiment,  move  to  the  left,  it  means  that  the  internal  rectus  of  the 
right  eye  and  the  external  rectus  of  the  left  are  contracting,  whereas 
the  external  rectus  of  the  former  and  the  internal  rectus  of  the  latter 


848  THE    CENTRAL   NERVOUS   SYSTEM 

are  becoming  reciprocally  inhibited,  the  other  muscles  participating 
to  a  slight  degree.  If  all  the  nerves  to  the  extraocular  muscles  of  the 
right  eye  are  cut  except  the  sixth,  which  supplies  the  external  rectus, 
it  will  be  found  that  this  eye  looks  permanently  toward  the  right  side ; 
that  is,  an  external  strabismus  is  produced.  If  now  the  right  cortex  is 
stimulated,  both  eyes  will,  as  before,  move  to  the  left,  although  the 
right  eye  will  not  move  farther  than  the  middle  line.  Its  movement  as 
far  as  this,  however,  must  evidently  be  due  to  an  active  inhibition  of  the 
external  rectus  muscle,  for  none  of  the  other  muscles  can  act  since  the 
nerves  are  cut. 

The  experiment  of  conjugate  deviation  brings  out  another  point  re- 
garding cerebral  localization — namely,  that  the  muscles  which  ordinarily 
act  along  with  muscles  on  opposite  sides  of  the  body,  are  innervated 
from  both  sides  of  the  cerebral  cortex.  This  applies  not  only  to  the 
movements  of  the  eyes,  but  to  the  respiratory  and  other  movements  of 
the  neck  and  trunk.  Destruction  of  the  trunk  center  of  the  cerebral 
cortex  on  one  side  does  not  produce  any  paralysis,  while  stimulation  in 
this  region  produces  an  equal  movement  on  both  sides.  We  may  say 
therefore  that  bilaterally  acting  muscles  are  innervated  from  both  sides 
of  the  cerebral  cortex. 

The  movements  produced  by  stronger  stimulation  of  the  cerebrum  do 
not  remain  localized,  and  they  persist  for  some  time  after  the  stimulus 
has  been  removed.  Still  further  increase  in  the  strength  of  the  stimulus 
may  cause  the  contraction  to  spread  until  it  affects  all  parts  of  the 
body,  giving  rise  to  a  convulsion.  There  are  two  types  of  contraction 
during  this  convulsion,  the  first  being  a  strong  tonic  contraction,  which 
outlasts  the  stimulus  for  some  time  and  then  gives  way  to  a  series  of 
clonic  contractions,  occurring  at  intervals  of  from  six  to  ten  per  second, 
and  gradually  getting  slower  as  the  fit  dies  away.  The  convulsion  al- 
ways starts  in  the  muscle  group  represented  by  the  cortical  center  that 
is  being  stimulated.  Thus,  if  the  hand  area  is  the  seat  of  stimulation, 
the  convulsions  begin  in  the  muscles  of  the  hand ;  then  they  spread  to 
the  muscles  of  the  forearm  and  shoulder  on  the  same  side,"  and  then  to 
the  face,  the  trunk,  and  the  leg;  and  if  the  stimulus  is  strong  enough, 
they  may  spread  to  the  opposite  side  and  thus  involve  the  whole  body. 
This  "march"  of  the  convulsion  depends  upon  the  overflow  of  the  stimu- 
lus on  to  the  various  centers  of  the  brain,  and  the  pathways  through  which 
it  occurs  seem  to  be  located  in  the  subcortical  centers,  for  the  spread 
is  not  prevented  by  isolating  the  cortical  centers  from  one  another  by 
cuts  encircling  them,  or  by  division  of  the  corpus  callosum.  Never- 
theless, the  centers  do  in  some  way  become  involved  in  the  spread,  as 
is  indicated  by  the  fact  that  the   complete   excision   of  one   of  them 


CEREBRAL    LOCALIZATION  849 

will    exclude   the    corresponding   muscular   area   from    participation    in 
the  fit. 

CLINICAL  OBSERVATIONS 

The  foregoing  results  obtained  by  experimental  stimulation  in  animals, 
are  very  similar  to  the  symptoms  observed  in  man  when  the  cerebral 
cortex  is  stimulated  by  the  pressure  on  it  of  a  meningeal  tumor  or  a 
spicule  of  bone.  Such  stimulation  causes  contraction  in  the  correspond- 
ing muscular  area;  the  contraction  then  spreads  to  neighboring  groups 
of  muscles,  and  may  ultimately  involve  the  whole  musculature  of  the 
body  in  a  convulsive  fit,  like  that  produced  in  animals.  This  is  known 
as  Jacksonian  epilepsy,  and  it  is  to  be  distinguished  from  ordinary 
epilepsy  by  the  fact  that  the  patient  does  not  become  unconscious  dur- 
ing the  fit.  Like  ordinary  epilepsy,  however,  the  Jacksonian  type  is 
usually  preceded  by  a  peculiar  sensation  of  numbness  or  tingling  in  the 
area  that  is  to  show  the  first  contraction.  One  of  the  greatest  achieve- 
ments of  modern  brain  surgery  is  the  cure  of  Jacksonian  epilepsy,  by 
trephining  the  skull  over  the  affected  center  and  removing  the  meningeal 
tumor  or  spicule  of  bone  which  is  responsible  for  the  stimulation.  To 
enable  the  surgeon  to  locate  exactly  the  position  of  the  irritating  body, 
it  is  necessary  to  examine  the  patient  very  closely  as  to  the  muscular 
group  which  is  initially  affected  during  the  convulsions,  and  then  to 
examine  an  outline  map  of  the  cerebral  hemisphere  indicating  the  po- 
sition of  the  various  motor  and  sensory  areas  as  deduced  mainly  from 
experiments  on  the  higher  monkeys  and  verified  by  the  experience 
gained  by  previous  operations.  Topographic  maps  indicating  the  sur- 
face markings  corresponding  to  the  various  convolutions  of  the  cerebrum 
must  also  be  used.  In  such  operations  the  surgeon  often  has  the  op- 
portunity of  experimentally  verifying  the  position  of  various  centers. 


CHAPTER  XCVI 
CEREBRAL  LOCALIZATION  (Cont'd) 

SENSORY  CENTERS 

That  the  motor  centers  are  located  in  the  areas  which  we  have  just 
described  does  not  indicate  that  the  nerve  cells  of  the  centers  normally 
dominate  the  reflex  movements  which  their  stimulation  elicits.  The  motor 
centers,  strictly  speaking,  are  the  anterior  horn  cells  of  the  spinal  cord; 
and  the  so-called  motor  centers  of  the  cerebral  cortex  must  really  repre- 
sent nothing  more  than  internuncial  neurons  between  the  entering  and 
leaving  paths  concerned  in  reflex  movements.  They  are  only  links  in 
the  long  cerebral  chain — way-houses  on  the  reflex  cerebral  pathway. 
According  to  this  view  we  should  expect  that  these  centers  would  be 
the  ultimate  recipients  of  sensation,  as  well  as  the  distributors  of  motor 
impulses;  sensorimotor,  they  have  been  called.  Such,  however,  is  not 
the  case,  for  Sherrington  has  shown  that  the  centers  most  directly  con- 
cerned in  the  reception  of  sensory  impulses  are  not  located  in  front  of 
the  Rolandic  fissure  but  immediately  behind  it  in  the  ascending  parietal 
or  postcentral  convolution.  Electrical  stimulation  in  this  region  does 
not  evoke  any  immediate  response,  at  least  if  the  stimulus  is  not  too 
strong.  A  movement  indirectly  due  to  the  receipt  of  a  sensation  may 
be  elicited  by  a  strong  stimulus,  just  as  is  the  case  when  the  visual  cen- 
ter in  the  occipital  lobe  is  strongly  stimulated,  producing  secondary 
movements  of  the  eyes. 

Histologic,  experimental  and  clinical  evidence  has  been  furnished  to 
support  this  location  of  the  chief  sensory  center.  The  clinical  evidence 
was  furnished  by  Harvey  Cushing,14  who  induced  two  patients  in  whom 
this  part  in  the  brain  was  exposed  to  allow  him  to  stimulate  it  while  they 
-were  in  a  conscious  state.  As  the  result  of  the  stimulation  of  the  post- 
central convolution  definite  sensory  impressions  were  experienced,  consist- 
ing of  a  sensation  of  numbness  or  deadness  to  tactual  impressions,  but 
no  muscular  groups  underwent  movement  unless  the  precentral  con- 
volution was  stimulated.  During  these  movements,  moreover,  no  sen- 
sations were  experienced  by  the  patient  except  those  which  accompanied 
the  change  in  the  position  of  the  part  that  was  moved.  The  sensations 
which  are  thus  represented  on  the  cortex  are  those  of  touch  discrimina- 

850 


oebbbbAl  localization  851 

tion  and  those  relating  to  the  position  and  movements  of  the  muscles. 
Tain  and  temperature  sensations  do  not  seem  to  have  cortical  represen- 
tation. 

There  is  of  course  a  close  association  between  sensory  and  motor  cen- 
ters, as  is  illustrated  in  the  experiment  described  elsewhere  under  the 
head  of  apesthesia  (page  838),  in  which  it  will  be  remembered  that  the 
complete  section  of  all  the  posterior  roots  of  an  extremity  renders  the 
part  as  effectively  paralyzed  for  volitional  movement  as  it  Mould  have 
been  had  the  motor  roots  themselves  been  cut.  Afferent  impulses  are 
therefore  necessary  for  the  efficient  volitional  control  of  the  muscular 
movements. 

SENSE  CENTERS 

Attempts  to  locate  exactly  the  position  on  the  cerebral  cortex  where 
impressions  of  the  projicient  sensations — vision,  hearing,  etc. — are  re- 
ceived are  of  course  more  or  less  difficult  because  of  the  fact  that  the 
experiments  have  to  be  performed  on  dumb  animals.  Nevertheless  some 
information  can  be  gleaned  from  the  results  of  ablation  and  stimulation 
of  various  parts  of  the  cortex,  ablation  causing,  for  example,  definite 
evidence  either  of  blindness  or  of  deafness,  and  stimulation  causing 
movements  of  the  eyes  or  ears  similar  to  those  ordinarily  observed  when 
these  organs  are  stimulated  in  the  usual  way. 

The  auditory  center  is  located  in  the  back  part  of  the  superior  temporal 
convolution.  Stimulation  of  this  area  in  animals  causes  a  pricking  up 
of  the  ear  on  the  opposite  side  as  if  the  animal  heard  a  sound.  Clinical 
observation  has  confirmed  this  conclusion. 

The  visual  center  is  located  in  the  occipital  lobe.  It  is  important  to  re- 
peat again  that  there  are  two  centers  on  the  cerebral  cortex  concerned  in 
vision:  the  frontal  visual  center,  located  as  we  have  seen  in  the  frontal 
lobe,  and  the  so-called  visual  center  itself,  located  in  the  occipital  lobe. 
Stimulation  of  the  frontal  visual  center  produces  a  prompter  movement 
of  the  eyes  than  does  stimulation  of  the  occipital  center,  indicating  that 
the  frontal  center  has  the  immediate  control  of  the  muscular  movements, 
whereas  the  occipital  lobe  is  probably  concerned  in  the  adjustment  of 
the  muscular  reactions  which  are  necessary  in  controlling  the  eye  move- 
ments, so  that  the  objects  may  be  properly  viewed  and  judgments 
formed,  by  the  extent  of  the  movements,  of  its  distance,  position,  etc. 
The  actual  response  to  stimulation  of  the  occipital  centers  shows  that 
the  lobe  on  one  side  is  connected  with  the  corresponding  half  of  each 
retina,  the  fovea  centralis  being,  however,  connected  with  both  lobes. 


852 


THE    CENTRAL   NERVOUS    SYSTEM 


ASSOCIATION  AREAS 

The  brilliant  outcome  of  the  researches  conducted  by  the  experimental 
method  in  enabling  us  to  locate  the  chief  motor  and  sensory  areas  of 


r    s    X 


x  \  >  Vil 


Motor  leg  area 


fj-'i 


i 


V  A      k 


Yisuosensory 


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TTTTTT 


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1       ► 


>        l*Y  I 

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Visuopsychic 


Fig.    220. — Three    sections    through    different    parts    of    the    cerebral    cortex.       For    description    see 
content.      (Redrawn    from    Starling.) 

the  cerebral  cortex  leaves  yet  uncharted  those  vast  areas  lying  between 
them  which  do  not  respond  in  any  definite  way  to  artificial  stimulation, 
and  the  ablation  of  which  results  only  in  more  or  less  indefinite  symp- 


CEREBRAL    LOCALIZATION 


853 


loins,  in  order  to  discover  the  exad  Function  of  these  areas,  it  has  been 
necessary  to  employ  an  entirely  different  method — that  of  histologic 
and  embryologic  examination.  When  the  patterns  of  the  gray  cortex 
are  compared  with  the  habits  of  the  animals,  in  different  groups  of 
animals   (phylogenetie  study),  or  even  in  different  individuals  of  the 


Fig.  221. — The  location  of  the  chief  motor  and  sensory  areas  on  the  outer  (A)  and  mesial  (S) 
aspects  of  the  human  brain,  as  determined  by  the  microscopic  structure  of  the  cortex.  These 
maps  are  only  approximately  accurate,  but  they  indicate  in  a  general  way  how  the  cortex  is 
structurally    composed.      (From    Starling   after    Campbell.) 


same  group  (ontogenetic  study),  much  useful  knowledge  concerning 
cerebral  localization  can  also  be  gained.  In  the  human  animal  much 
progress  is  being  made  by  comparing  the  structural  pattern  of  the  cor- 


854  THE    CENTRAL    NERVOUS   SYSTEM 

tex  in  different  parts  of  the  normal  brain  with  that  found  in  the  brain 
of  psychopathic  individuals  whose  mental  symptoms  have  heen  care- 
fully studied  before  death.* 

For  the  purpose  of  this  work  it  is  necessary  to  recognize  several 
laminae  or  layers  of  nerve  colls  and  nerve  fibers  composing  the  cortex. 
The  most  practical  division  is  represented  in  Fig.  220,  and  is  as  follows: 
(1)  a  narrow  superficial  layer  of  nerve  fibers,  with  a  few  scattered  cells — 
the  outer  fiber  lamina  or  molecular  layer;  (2)  a  much  wider  layer  of  small, 
medium  and  large  pyramidal  cells — the  outer  or  pyramidal  cell  lamina; 
(3)  a  layer  of  granules — the  middle  cell  lamina:  (4)  an  inner  layer 
of  nerve  fibers,  sometimes  containing  large  solitary  cells  (Betz  cells)  — 
the  inner  fiber  lamina;  (5)  a  layer  of  polymorphic  cells — the  inner  cell 
lamina.  This  five-layer  type  undergoes  structural  modifications  in  the 
different  regions  of  the  cortex,  and  these  modifications  possess  a  dis- 
tinct functional  significance.  The  only  part  of  the  brain  in  which  they 
can  not  be  recognized  is  the  hippocampus  and  the  pyriform  lobe.  Based 
on  the  relative  thickness  of  these  layers  maps  of  the  cerebral  cortex 
have  been  produced.  The  most  important  are  those  of  Brodmann  and 
Campbell,  of  which  the  latter  is  reproduced  in  Fig.  221.  Two  re- 
gions can  be  very  definitely  located;  namely,  the  precentral  or  Betz- 
cell  area,  and  the  visual  or  visuosensory  area  of  Campbell.  Surrounding 
the  visuosensory  area  is  a  definite  visuopsychic  area,  and  similarly, 
bordering  on  the  precentral  is  the  so-called  intermediate  precentral 
area.  At  the  very  front  of  the  frontal  lobe  is  the  prefrontal  area.  Post- 
central and  intermediate  postcentral  areas  are  indicated,  but  the  re- 
mainder of  the  center  is  undefined. 

Reasoning  from  phylogenetic  and  ontogenetic  data,  we  can  assign  to 
each  of  these  lamina?  a  functional  significance,  which  according  to  Bol- 
ton is  as  follows:  The  outer  cell  lamina  (pyramidal  cell  lamina)  proba- 
bly constitutes  the  "higher  level"  basis  for  the  carrying  on  of  the  higher 
or  psychic  cerebral  functions.  It  is  a  prominent  feature  of  the  human 
cortex,  the  last  cell  layer  to  be  evolved,  and  the  one  which  undergoes 
retrogression  most  readily.  During  development  it  rapidly  attains  ma- 
turity in  the  visuosensory  area,  next  in  the  visuopsychic,  and  only  later 
in  the  prefrontal  region.  In  the  visuopsychic  area  it  is  practically  of 
the  same  depth  as  in  the  visuosensory,  whereas  in  the  prefrontal  region  it 
develops  according  to  the  mental  capacity  of  the  animal.  In  patients  ex- 
hibiting symptoms  of  dementia  this  layer  of  cells  is  distinctly  deficient. 
These  facts  indicate  that  the  outer  or  pyramidal  cell  lamina  "subserves 
the  psychic  or  associational  functions  of  the  cerebrum" — (Bolton). 


*An  excellent  account  of  the  physiologic  basis  for  such  work  is  given  by  Bolton  in  Leonard  Hill's 
Further  Advances  in  Physiology.  We  have  made  free  use  of  this  article  in  the  present  review  and 
would    strongly    recommend    its    perusal    by    any    who    may    desire    further    information.19 


CEREBRAL    LOCALIZATION  b-)-i 

The  middle  cell  lamina  is  much  hypertrophied  in  the  so-called  projec- 
tion areas  of  the  cerebrum — for  example,  in  the  visuosensory  area  (sec 
Fig.  20),  where  it  is  so  thick  that  it  is  usually  described  as  being  divided 
into  two  parts  by  a  narrow  fiber  band  (the  line  of  Gennari).  Diminution 
in  the  layer  occurs  in  the  visuosensory  area  in  long-standing  cases  of 
atrophy.  "It  seems  therefore  primarily  to  subserve  the  function  of  re- 
ceiving afferent  impressions  whether  these  arrive  directly  from  the  lower 
sensory  neurons  or  indirectly  through  other  regions  of  the  cerebrum." 

The  fifth  or  inner  cell  lamina  is  the  first  to  become  differentiated,  and 
it  is  of  extremely  constant  depth  in  the  adult.  It  is  not  much  affected  in 
amentia,  unless  when  this  is  very  severe,  as  in  patients  who  are  unable 
to  carry  on  the  ordinary  animal  functions.  In  short,  "it  subserves  the  lower 
voluntary  and  instinctive  activities  of  the  animal  economy" — (Bolton). 

Taking  the  results  as  a  whole,  it  appears  that  the  region  of  the  cortex 
behind  the  Rolandic  fissure  consists  of  sensory  areas  and  association 
areas  which  may  be  immediately  connected  with  them  (visuopsychic  and 
intermediate  postcentral)  or  more  removed  (in  parietal  lobe).  The  por- 
tion in  front  of  the  Rolandic  fissure,  on  the  other  hand,  contains  the 
efferent  areas,  of  which  the  precentral  may  be  regarded  as  of  lowest 
grade.  The  motor  discharges  from  it  are  conditioned  upon  impulses 
coming  partly  from  the  adjacent  intermediate  precentral  area,  in  which 
again  are  elaborated  those  received  from  the  sensory  areas,  and  partly 
from  those  coming  from  the  prefrontal  region,  which  is  the  most  com- 
plex zone  of  association.  This  last  is  indeed  the  supreme  dominating 
area.  It  coordinates  or  integrates  the  activities  of  the  other  association 
areas  and  may. be  considered  as  the  seat  of  the  intellect.  The  evidence 
for  this  high  evolution  of  the  prefrontal  area  is  very  strong.  It  is  the 
last  portion  of  the  cortex  to  be  evolved  and  the  first  to  undergo  retro- 
gression. In  idiots  and  imbeciles  the  thickness  of  the  pyramidal  cell 
layer  in  this  region  is  directly  proportional  to  the  mental  power,  and 
in  dementia  degrees  of  retrogression  occur  that  vary  directly  with  the 
existing  grade  of  dementia.  In  normal  brains  this  layer  is  the  very 
one  which  varies  in  depth  in  different  individuals.  Along  with  its  high 
development  in  the  brain  of  man,  as  compared  writh  that  of  other  ani- 
mals, goes  hand  in  hand  a  great  increase  in  the  other  association  areas. 
Thought  is  the  product  of  integration  between  these  various  associa- 
tion areas,  and  articulate  and  written  language  the  outward  manifesta- 
tion of  the  process.  It  is  owning  to  the  relatively  great  extent  and  com- 
plexity and  constant  development  of  the  prefrontal  lobe  that  man  so  far 
excels  even  the  highest  apes  in  his  intellectual  activity,  and  it  is  owning 
to  the  relative  functional  development  of  this  lobe  that  individuals  dif- 
fer from  one  another  in  their  mental  powTers. 


CHAPTER  XCVII 
CONDITIONED  AND  UNCONDITIONED  REFLEXES 

In  studying  the  reflexes  in  the  spinal  animal,  we  have  seen  that  the 
effect  of  a  given  stimulus  or  of  different  stimuli  is  predictable  with 
absolute  certainty.  There  is  a  fatality  in  the  responses.  When  the 
higher  centers  are  included  in  the  reflex  arc,  the  reflexes  become  modi- 
fied or  inhibited  by  events  occurring  in  other  parts  of  the  central  ner- 
vous system  and  the  results  come  to  be  more  and  more  unpredictable. 
The  reflex  comes  to  be  a  conditioned  reflex  (Pavlov).  Studies  of  the 
circumstances  affecting  these  conditioned  reflexes  really  constitute  a 
study  of  the  function  of  the  higher  centers  in  the  brain.  Since  such 
experiments  must  be  performed  on  the  lover  animals,  we  are  limited  in 
the  investigation  to  motor  responses,  for  we  have  no  way  whatever  of 
studying  the  subjective  sensations  produced.  The  motor  phenomena  by 
which  the  animal  may  express  its  sensations  can  be  interpreted  by  us 
only  in  terms  of  psychologic  ideas  that  in  large  part  are  derived  from 
our  own  experiences.  Obviously  the  conclusions  that  can  be  drawn 
are  subject  to  very  great  sources  of  error,  and  it  must  be  considered  as 
one  of  the  greatest  advances  of  modern  physiology  that  Pavlov  and 
others  should  have  succeeded  in  evolving  methods  by  which  Ave  may  ar- 
rive at  conclusions  regarding  the  nature  of  certain  of  the  integrations 
that  occur  in  the  higher  centers  of  the  nervous  system  preceding  the 
motor  manifestations  by  which  the  animal  expresses  its  sensations. 

The  methods  employed  for  the  study  of  these  higher  integrations  of 
the  central  nervous  system  all  depend  on  the  reactions  of  the  animal 
that  are  associated  with  the  taking  of  food.  When  the  food  is  actu- 
ally placed  in  the  mouth,  it  excites  a  secretion  of  saliva,  whatever  the 
circumstances  may  be.  This  is  an  unconditioned  reflex.  Suppose,  how- 
ever, that  every  time  food  is  given  a  particular  sound  is  made ;  after 
some  time  it  will  be  found  that  the  occurrence  of  the  sound  alone  is 
sufficient  to  cause  a  secretion  of  saliva.  In  other  words,  a  conditioned 
reflex  has  been  formed.  Similarly,  sight  or  smell  or  any  other  type  of 
sensation  may  be  made  the  excitant  for  the  conditioned  reflex.  The 
secretion  now  becomes  psychic  instead  of  merely  physiologic.  To  quote 
Bayliss:  "Any  phenomenon  of  the  outer  world  for  which  the  animal  in 
question  possesses  appropriate  receptors  can  be  drawn  into  temporary 

856 


CONDITIONED   AND   UNCONDITIONED   REFLEXES  857 

association  with  salivary  secretion,  so  that  it  becomes  an  exciter  of  se- 
cretion if  only  it  has  been  frequently  presented  at  the  same  time  with 
the  unconditioned  reflex  stimulus,  food  in  the  mouth." 

Work  along  Hues  similar  to  that  devised  by  Pavlov  has  more  recently 
been  undertaken  by  students  of  animal  behavior,  who  have  utilized  the 
acquired  habits  of  an  animal  in  searching  for  its  food  in  order  to  study  the 
influence  of  conditioning  circumstances  on  its  procedure.  The  advantage 
of  this  method  depends  mainly  on  the  fact  that  it  can  be  applied  to  all 
groups  of  animals.  In  carrying  out  such  an  observation,  the  animal  is 
placed  in  one  compartment  of  a  cage,  from  which  it  is  then  released  to 
a  second  compartment,  "the  end  of  which  is  divided  into  two  passage- 
ways,  one  leading  to  food,  the  other  leading  to  some  compartment  in 
which  the  animal  is  punished  for  its  mistake  as  by  receiving  an  electric 
shock.  Objects  such  as  colored  lights  are  placed  in  the  different  pas- 
sageways, and  the  animal  by  repeated  trial  comes  ultimately  to  learn 
which  particular  colored  light  signifies  the  passage  along  which  he 
will  receive  food.  A  reflex  has  therefore  become  established  conditioned 
on  the  particular  colored  light. 

On  account  of  the  unavailability  of  his  publications,  it  is  impossible 
at  present  to  give  any  complete  account  of  Pavlov's  discoveries.  A  few 
facts,  however,"  are  of  such  importance  that  it  is  necessary  for  us  to 
state  them  here  as  far  as  we  know  them.  (See  Bayliss,  Physiology.)  Two 
mechanisms  seem  to  be  concerned  in  the  conditioned  reflexes:  (1)  that 
of  temporary  association,  and  (2)  that  of  analysis.  Temporary  associa- 
tion is  well  illustrated  in  the  above  experiment  in  which  the  secretion  of 
saliva  is  induced  by  a  sound.  Temporary  association  of  the  sound  with 
the  secretion  of  the  saliva  may  readily  be  inhibited  by  all  kinds  of  ex- 
ternal phenomena;  thus,  if  the  dog's  attention  becomes  diverted  while 
the  conditioned  reflex  is  being  stimulated,  the  response  does  not  occur. 
In  a  dog  that  had  been  trained  to  secrete  saliva  to  the  sound  of  a  par- 
ticular metronome  beat,  inhibition  occurred  one  day  because,  just  as 
the  dog  was  being  presented  with  the  food,  the  laboratory  servant  made 
a  noise  outside  of  the  building  which  diverted  the  animal's  attention. 
The  conditioned  reflex  may  also  be  interfered  with  by  internal  inhibi- 
tion, which  is  illustrated  by  experiments  in  which,  after  a  dog  has  been 
trained  to  respond  to  a  given  conditional  reflex,  several  occasions  follow 
when  food  is  not  given  to  the  animal  after  the  particular  sensation  to  which 
it  has  been  trained  to  respond.  The  condition — for  example,  a  sound — loses 
its  effect.  This  is  internal  inhibition,  but  it  is  a  temporary  condition 
since  the  reflex  returns  of  itself  after  a  period  of  rest. 

These  experiments  illustrate  what  is  meant  by  the  formation  of  tem- 
porary associations  occurring  in  conditioned  reflexes,  but  in  order  that 


858  THE   CENTRAL    NERVOUS   SYSTEM 

there  may  be  a  fine  discrimination  between  those  stimuli  which  shall 
and  those  which  shall  not  serve  to  call  forth  the  conditioned  reflex,  an- 
other mechanism  becomes  involved — that  of  analysis.  This  is  performed 
by  a  sense  organ  the  function  of  which  is  to  separate  and  distinguish 
the  complicated  phenomena  of  the  outer  world.  For  example,  it  has 
been  proved  that  small  differences  in  the  pitch  of  a  musical  note  may 
determine  whether  or  not  a  conditioned  reflex  will  be  excited  or  in- 
hibited, as  in  the  case  of  one  animal  that  was  trained  to  respond  by 
the  secretion  of  saliva  to  a  tuning  fork  vibrating  at  100  per  second.  It 
was  found  that  no  secretion  was  produced  by  a  tuning  fork  vibrating 
at  104  or  at  96.  Much  work  has  also  been  done' with  the  skin  receptors. 
Thus,  when  a  given  spot  of  skin  is  stimulated  every  time  that  food  is 
presented,  this  becomes  an  active  spot  for  the  conditioned  reflex.  At 
the  same  time  another  spot  may  be  stimulated  so  as  to  be  associated  by 
the  animal  with -the  nonpresentation  of  food;  it  is  a  conditioned  reflex 
for  no  food,  and  is  associated  with  the  absence  of  salivary  secretion. 

By  comparing  the  responses  from  active  and  inactive  spots  when  both 
are  stimulated  either  simultaneously  or  at  close  intervals,  much  can 
be  learned  concerning  the  delicacy  of  appreciation  for  external  stimuli 
and  the  influence  of  the  inhibitory  on  the  excitatory  process.  Bayliss 
cites  the  following  experiment.  Along  a  series  of  spots  on  the  skin 
of  the  leg  five  devices  are  arranged  for  producing  equal  mechanical 
stimulations  of  the  skin.  The  four  uppermost  of  these  are  made  active 
spots  for  the  salivary  reflex,  and  the  lowest  one  inactive — that  is,  when- 
ever it  is  stimulated  no  food  is  presented.  Let  us  suppose  that  upon 
administering  mechanical  stimuli  of  equal  intensity  to  each  of  the  active 
four  spots,  a  certain  amount  of  saliva  is  produced  in  a  certain  time;  if 
now  the  inactive  spot  is  stimulated  and  then  thirty  seconds  later  one 
of  the  uppermost  spots,  there  will  be  no  secretion.  The  previous  stimu- 
lation of  the  inactive  spot  must  evidently  have  caused  an  inhibition  to  be 
set  up  in  the  nerve  centers  concerned  in  the  reflex.  This  inhibition  only 
gradually  passes  away,  disappearing  first  in  the  spot  farthest  removed 
from  that  made  inactive,  but  it  may  take  several  minutes  before  all  the 
active  spots  have  reacquired  their  original  sensitivity. 

The  persistence  of  the  inhibition  produced  by  stimulating  the  inac- 
tive spot  in  the  above  experiment  indicates  an  important  factor  in  con- 
nection with  the  production  of  conditioned  reflexes.  For  example,  an 
animal  can  be  trained  to  know  that  in  a  certain  number  of  minutes  after 
the  sound  of  a  given  bell  food  will  be  presented  to  him ;  the  condi- 
tioned reflex  will  become  established  so  that  he  salivates  at  exactly 
the  same  time  after  the  bell  is  sounded.  Something  must  be  going  on 
in  the   centers  during  this   time — something  inhibiting   the   reflex.     If 


CONDITIONED    AND    UNCONDITIONED    REFLEXES  859 

during  this  interval  of  inhibition  some  other  sensory  stimulus  is  applied, 
it  will  he  likely  to  cu1  short  the  inhibition;  in  other  words,  it  produces 
mi  inhibition  of  inhibition,  so  that  the  secretion  of  saliva  occurs. 

Another  most  curious  combination  of  conditioned  stimuli  is  illustrated 
in  the  following  experiment.  Suppose,  tor  example,  that  a  given  light 
and  sound  are  each  separately  made  a  stimulus  for  a  conditioned  reflex, 
hut  that  when  they  occur  together  there  is  no  reflex.  Suppose  now  that 
while  one  of  these  active  stimuli  is  being  presented,  the  other  stimulus 
is  also  presented;  the  result  will  he  that  the  secretion  produced  by  the 
one  stimulus  will  stop.  Evidently,  although  each  is  in  itself  a  stimulus, 
acting  together  they  cause  inhibition. 

By  studying  the  conditioned  reflexes  after  a  certain  part  of  the  cere- 
bral cortex  has  been  removed,  it  has  been  found  that  the  power  of  estab- 
lishing certain  kinds  of  conditioned  reflexes  becomes  abolished,  while 
that   for  others  is  retained. 


CHAPTER  XCVIII 

THE  HIGHER  FUNCTIONS  OF  THE  CEREBRUM  IN  MAN; 

APHASIA 

The  study  of  the  higher  functions  of  the  cerebrum  leads  us  to  the  border- 
land between  physiology  and  psychology,  but  into  this  vast  and  relatively 
unexplored  field  we  can  not  venture  here,  unless  just  far  enough  to  gain  a 
suitable  vantage  point  from  which  to  understand  the  pathology  of  the 
condition  known  as  aphasia*  As  we  have  seen  from  our  studies  on  cerebral 
localization,  the  cerebrum  must  be  regarded  as  a  great  sensorimotor  gan- 
glion, whose  functional  activities  are  indicated  by  various  movements. 
These  movements  may,  in  general,  be  classified  as  objective  indications 
either  of  feeling  and  emotion  or  of  intelligence.  Although  both  classes  are 
evident  in  all  animals,  it  is  particularly  in  the  case  of  man  that  the  evi- 
dences of  intelligent  activity  are  especially  prominent,  since  they  include 
gesticulation  and  the  muscular  activities  required  in  spoken  and  written 
language.  The  movements  that  express  emotional  conditions  are  evolved 
earlier  and  from  lower  planes  than  those  of  intellectual  activity.  Thus, 
very  young  infants  "make  faces"  when  there  is  reason  to  believe  they 
feel  pain,  and,  as  they  develop,  their  power  of  expressing  emotion  is 
evolved  long  before  they  present  evidence  of  intelligent  motor  activity, 
and  still  longer  before  they  can  articulate  words. 

The  phenomenon  of  human  psychic  activity  which  is  of  greatest  im- 
portance is  that  of  language,  and  to  understand  the  nature  of  the  cerebral 
integration  required  to  produce  it,  we  must  briefly  consider  the  cerebral 
processes  involved  in  the  intellectual  development  of  the  infant.  The 
first  step  in  this  development  is  the  storing  away  in  projection  centers  of 
memories  of  the  sensations  which  these  centers  have  received.  For  ex- 
ample, when  the  child  looks  at  a  bell,  there  is  stored  in  the  visual  center  a 
memory  of  the  shape  of  the  bell,  and  when  the  bell  moves  so  as  to  produce 
sound,  this  also  is  stored  as  a  sound  impression  in  the  auditory  center. 
Likewise,  when  he  touches  the  bell  impressions  of  its  hardness  and  smooth- 
ness and  temperature  are  stored  in  the  centers  for  cutaneous  sensations. 
At  first  each  of  these  memory  impressions  occupies  an  isolated  position; 
but  later,  association  tracts  open  up  between  them,  so  that  the  calling 


*Free   use    of    Bolton's    article   is    made    in    this    chapter. 

860 


HIGHER   FUNCTIONS   OP    THE    CEREBRUM    IN    MAN;    APHASIA  861 

forth  of  one  memory  impression  is  associated  with  others,  and  the  child 
comes  to  be  able  to  associate  the  appearance  or  image  of  the  bell  with  a 
certain  sound  and  with  certain  sensations  of  hardness,  rotundity,  etc.  This 
preliminary  use  of  observation  is  known  as  perception.  It  involves  the 
fusion  of  direct  sensations  as  well  as  their  correlation  with  memory  im- 
pressions of  former  sensations.  The  number  and  variety  of  the  latter 
called  into  activity  by  a  particular  sensation  will  obviously  vary  at  dif- 
ferent times.  On  seeing  a  bell,  for  example,  a  child  may  associate  it  with 
sound  on  one  occasion,  and  on  the  next  with  the  feeling  of  the  bell.  On 
account  of  this  difference  in  the  detail  of  the  method  of  association,  it  is 
evident  that  perception  must  be  a  product  of  cerebral  integration  rather 
than  one  depending  on  memory  impressions  stored  in  the  isolated  centers. 
It  is  a  complicated  process  with  an  infinite  variety  of  possibilites  as  to  the 
exact  way  in  which  it  is  integrated  on  each  occasion. 

The  act  of  perception,  however,  becomes  considerably  simplified  in  the 
higher  animals  by  the  laying  down  of  short-cut  paths  of  association. 
These  are  formed  first  of  all  with  the  auditory  center,  in  which  the  memory 
impression  of  an  articulated  sound  representing  the  object — for  example, 
the  word  "bell" — is  stored  away.  The  child  comes  to  learn  that  this  par- 
ticular word  is  to  be  associated  with  the  memory  impressions  it  has  stored 
away  of  the  sound,  the  sight,  and  the  feeling  of  the  bell.  Similar  short-cut 
paths  later  become  developed  in  connection  with  the  visual  centers,  where 
a  certain  symbol,  like  the  word  "bell,"  is  presented  to  the  child  as  signi- 
fying all  the  other  attributes  of  bell.  In  its  most  highly  developed  form, 
therefore,  perception  may  be  described  as  the  act  of  calling  up  one  or 
more  sensorimemorial  images  when  a  name  is  seen  or  heard.    - 

Having  acquired  the  ability  to  integrate  sensorimemorial  impressions 
in  the  above  described  manner,  the  child  next  learns  to  integrate  the  motor 
centers  concerned  in  the  control  of  the  articulatory  apparatus  so  as  to 
produce  a  sound.  This  sound  is  the  word  indicating  the  object  involved 
in  the  integrating  process.  It  is  the  integration  necessary  to  produce  the 
sound  which  symbolizes  the  particular  object. 

When  the  power  of  understanding  and  producing  language  has  been 
acquired,  the  crowning  process  of  intellectual  development — the  forma- 
tion of  a  concept,  or  general  notion — becomes  evolved.  Thus,  the  evolu- 
tion of  a  general  name  will  include  a  number  of  particular  objects  or  acts. 
"This  process  of  conception  involves  the  revivification  of  numerous  sen- 
sorimemorial images  which  present  common  points  of  similarity" — (Bol- 
ton). It  is  relatively  a  simple  process  for  such  general  objects  as  animal, 
man,  building,  but  becomes  very  complex  for  such  abstract  concepts  as 
heaviness,  beauty,  etc.    It  is  obviously  a  process  to  which  no  one  cerebral 


862  THE  CENTRAL  NERVOUS  SYSTEM 

center  can  be  assigned.  The  outward  manifestation  of  the  conception  is 
spoken  or  written  language. 

Language  consists,  therefore,  in  an  extremely  complex  symbolic  system, 
involving  various  centers  and  association  tracts  in  the  cerebrum,  and 
capable  of  an  almost  infinite  degree  of  development  by  the  laying  down 
of  new  symbolic  systems.  Language,  indeed,  becomes  the  instrument  of 
thought,  practically  all  of  the  higher  intellectual  processes  being  dependent 
on  its  evolution.  In  this  connection  it  is  interesting  to  note  that  a  great 
number  of  individuals,  especially  those  who  do  not  read,  depend  on  the 
sense  of  hearing  for  the  acquisition  of  the  impressions  required  for  their 
psychic  development,  while  others  depend  on  the  sense  of  sight  for  the 
same  purpose. 

At  least  four  different  types  of  center  are  involved  in  the  integration 
of  language;  namely,  auditory,  visual,  chirographic,  and  articulatory.  We 
may  call  these  "word  centers,"  and  we  must  assume  that  they  lie  near  to 
the  auditory,  visual  and  general  sensory  projection  areas  of  the  cortex. 
To  understand  and  to  be  able  to  produce  spoken  and  written  language,  it 
is  necessary  that  all  these  four  word  centers  participate  through  associa- 
tion tracts,  although  the  meaning  of  a  word  may  be  perceived  without  all 
of  them  being  involved. 

PSYCHOPATHOLOGICAL  APPLICATIONS 

.  In  the  study  of  mental  diseases  the  most  important  conclusion  which 
we  can  draw  from  the  above  facts  is  that  language  is  essentially  a  sym- 
bolic mechanism  for  the  integration  of  sensorimemorial  images.  It  is 
therefore  the  symbolic  system  of  the  integrated  processes  of  the  brain;  it 
is  the  servant  of  thought.  "When,  as  is  often  the  case,  language  is  used 
without  the  proper  exercise  of  thought,  it  becomes  merely  an  automatic 
affair.  A  practical  deduction  from  these  facts  is  that  any  considerable 
derangement  of  the  language  mechanism  must  necessarily  involve  some 
interference  with  the  complicated  processes  of  association  that  go  to  make 
up  the  psychic  function. 

These  considerations  naturally  lead  us  to  the  subject  of  aphasia.  It  has 
been  usual  to  distinguish  three  varieties  of  this;  namely,  motor  aphasia, 
sensory  aphasia,  and  anarthria.  In  motor  aphasia  the  patient,  although 
he  understands  what  is  said  to  him,  is  unable  to  speak,  and  the  intellectual 
powers  are  little,  if  at  all,  impaired.  In  sensory  aphasia  speech  is  possible 
in  a  more  or  less  intelligible  manner,  but  there  is  a  distinct  impairment  of 
intelligence.  In  anarthria,  or  subcortical  aphasia,  the  only  disability  is  the 
loss  or  impairment  of  the  power  of  articulate  speech  because  of  some  lesion 
existing  in  the  center  coordinating:  the  lower  neurons  concerned  in  the 


HIG11KK    KCNCTIOXS   OF    THE    OEEEBRUM    [N    MAX;    APHASIA  863 

movements  of  the  laryngeal  and  tongue  muscles.  Pierre  Marie,  as  a 
result  of  xevy  extensive  experience  in  Paris,  has  shown  that  this  classifi- 
cation is  unjustified.  He  maintains  that  there  is  only  one  true  form  of 
aphasia,  and  that  such  a  thing  as  pure  motor  aphasia  as  ahove  defined 
does  not  exist,  the  condition  being  invariably  accompanied  by  intellectual 
impairment. 

Marie  points  out  that  the  various  claims  that  aphasia  may  exist  without 
intellectual  impairment  have  been  made  without  sufficient  investigation  of 
the  intellectual  status  of  the  patient.  He  shows  that  many  patients  suf- 
fering from  aphasia  if  asked  to  do  ordinary  things,  such  as  cough  or  spit 
or  raise  the  hand,  can  do  them  as  well  as  a  normal  individual,  but  that 
these  after  all  are  very  crude  acts  in  the  ordinary  performances  of  a  normal 
individual.  To  test  the  intellectual  powers  it  is  necessary  to  require  the 
patient  to  perform  acts  which  entail  a  considerable  amount  of  cerebral 
integration.  "We  must  ask  him  to  perform  some  sequence  of  events  such 
as  walking  several  times  in  one  direction,  then  in  another,  touching  cer- 
tain objects,  etc.,  or  better  still  we  should  observe  the  patient  closely  in  his 
business  transactions  and  everyday  routine  of  life  to  see  whether  he  does 
things  exactly  as  he  did  them  before.  It  is  always  possible  by  such  tests 
to  show  that  in  aphasia  the  mental  powers  have  become  distinctly  de- 
preciated. 

The  portion  of  the  cerebral  cortex  affected  in  aphasia  is  always  in  the 
neighborhood  of  the  so-called  area  of  "Wernicke,  which  is  closely  related  to 
the  visual  and  auditory  centers.  In  making  this  sweeping  conclusion, 
Marie  admits  that  cases  of  pure  word-blindness  but  not  of  word-deafness 
may  exist ;  that  is,  a  patient  still  retaining  his  intellectual  powers  may  lose 
his  ability  to  interpret  correctly  what  he  sees,  although  he  can  still  interpret 
accurately  what  he  hears. 

This  conclusion  conforms  exactly  with  those  of  the  psychophysiologists 
regarding  the  difference  in  the  language  mechanisms  of  educated  and  un- 
educated persons.  Language  is  learned  through  the  sense  of  hearing,  and 
it  is  only  by  later  education  that  more  is  learned  by  the  sense  of  sight ; 
that  is  to  say,  a  person  learns  to  read  only  after  he  has  learned  to  under- 
stand spoken  language.  "Word-blindness  may  therefore  occur  as  a  pure 
symptom,  and  is  less  likely  than  word-deafness  to  be  associated  with  ab- 
normal integrative  functions  of  the  cerebrum.  "Word-deafness  however  de- 
pends upon  a  lesion  involving  the  auditory  center;  it  necessarily  means 
disturbance  in  the  association  functions  of  the  cerebrum,  and  is  always 
accompained  by  a  certain  amount  of  mental  derangement. 

In  corroboration  of  these  facts  may  be  cited  the  well-known  fact  that 
a  deaf-mute  is  mentally  far  inferior  to  one  that  is  congenitally  blind. 
Loss  of  hearing  leads  to  more  serious  cerebral  disability  than  loss  of  sight. 


864  THE    CENTRAL   NERVOUS   SYSTEM 

To  quote  Bolton  again,  ' '  In  such  cases  deafness  is  therefore  a  more  serious 
deprivation  than  blindness,  as,  for  the  evolution  of  the  functional  activity 
of  the  cerebrum,  an  entirely  new  development  of  associational  spheres  to 
replace  those  normally  employed  for  auditory  and  spoken  language  has 
to  be  acquired.  In  the  case  of  congenital  or  early-acquired  blindness,  on 
the  other  hand,  the  complex  sphere  of  language,  with  all  its  psychic  com- 
ponents, can  be  employed  in  a  perfectly  normal  manner  and  almost  ex- 
actly as  it  is  brought  into  use  in  the  case  of  persons  who  neither  read  nor 
write." 

It  would  be  beyond  the  scope  of  this  work  to  go  into  the  clinical  and 
pathological  evidence  upon  which  Marie  bases  his  far-reaching  conclusions. 
Suffice  it  to  say  that  it  is  definitely  shown  that  the  old  contention  of  Broca, 
that  a  special  speech  center  exists,  is  entirely  unjustified  by  the  facts  of 
clinical  and  pathological  experience.  Broca,  it  will  be  remembered,  con- 
tended that  motor  aphasia  is  always  due  to  destructive  processes  occurring 
in  the  lower  portion  of  the  ascending  frontal  convolution  on  the  left  side, 
and  he  concluded  that  this  portion  of  the  cerebrum  represents  the  speech 
center.  Marie  has  shown,  however,  that  a  patient  may  show  distinct  evi- 
dence of  aphasia  without  any  lesion  involving  this  so-called  Broca  area, 
and,  on  the  other  hand,  that  cases  not  infrequently  occur  in  which  this  is 
completely  destroyed  without  any  evidence  of  aphasia.  Important  though 
this  discovery  of  the  inaccuracy  of  Broca 's  conclusion  is,  by  far  the  most 
important  conclusion  which  we  may  draw  from  Marie's  work  is  that,  since 
language  is  a  product  of  an  extended  integration  of  impressions  and 
memories  stored  in  different  parts  of  the  cerebrum,  it  is  not  so  likely  to  be 
interfered  with  by  destruction  of  any  one  of  the  centers  as  it  is  by  destruc- 
tion of  the  paths  which  connect  the  centers  with  one  another.  As  a  matter 
of  fact,  Marie  has  shown  that  in  cases  of  aphasia  the  lesion  is  nearly 
always  located  in  the  course  of  the  pathway  connecting  the  visual  and 
auditory  centers  with  the  other  centers  of  the  cerebrum ;  it  lies  around  the 
upper  end  of  the  fissure  of  Sylvius  in  the  region  which  in  previous  years 
had  been  considered  particularly  associated  with  the  condition  known  as 
sensory  aphasia.  Those  interested  in  this  subject  should  consult  Bolton's 
article. 


CHAPTER  XCIX 
FUNCTIONS  OF  THE  CEREBELLUM 

In  our  discussion  of  reflex  action  we  have  so  far  considered  only  those 
receptors  coming  from  the  exterior  of  the  body,  although  we  have  recog- 
nized that  a  considerable  number  of  the  afferent  nerve  roots  contain  fibers 
coming  from  receptors  situated  in  the  muscles,  the  tendons  and  the  joints, 
and  called  proprioceptors  because  they  respond  not  to  changes  in  the 
environment  but  to  alterations  in  the  body  itself.  "We  have  seen  that  the 
proprioceptors  consist  structurally  of  muscle  spindles  and  of  the  nerve 
endings  in  the  tendons  and  ligaments  and  synovial  membranes.  They  are 
receptors  that  are  attuned  to  respond  to  differences  in  tension  caused  either 
by  bulging  of  the  muscles  or  by  stretching  of  the  fibers  of  tendons  and 
ligaments. 

The  impulses  are  transmitted  in  the  spinal  cord,  either  by  the  posterior 
columns  or  by  the  lateral  cerebellar  tracts.  Those  traveling  by  the  pos- 
terior columns  are  sent  mainly  to  the  cerebral  cortex  of  the  opposite  side, 
whereas  those  in  the  cerebellar  tracts  enter  the  cerebellum  by  the  inferior 
peduncles  of  the  same  side.  The  cerebral  impulses  connect  with  neurons, 
which  transmit  the  impulse  back  again  to  the  cerebellum  of  the  opposite 
side,  so  that  ultimately  the  cerebellar  cortex  is  connected  with  the  spinal 
cord  of  the  same  side  either  directly  or  indirectly  through  the  cerebral 
cortex.  These  anatomic  facts  indicate  in  a  general  way  that  we  may 
expect  the  function  of  the  cerebellum  to  be  that  of  the  chief  nerve  center 
concerned  in  the  integration  of  the  proprioceptive  impulses  originated  by 
the  condition  of  contraction  or  relaxation  of  the  different  groups  of 
muscles  in  the  body,  and  by  the  amount  of  tension  existing  in  the  various 
tendons,  ligaments  and  other  membranes  surrounding  the  joints. 

Experimental  investigation  has  justified  these  expectations.  The  re- 
moval of  the  entire  cerebellum — an  operation  which  has  usually  been 
performed  on  birds,  particularly  pigeons,  because  of  the  ease  with  which 
it  can  be  done  in  these  animals — leads  immediately  to  a  condition  in  which 
muscular  activity  is  entirely  uncontrolled.  A  pigeon  after  this  operation 
flies  about  in  an  incoordinate  way,  turning  summersaults,  dashing  itself 
against  the  walls  of  its  chamber,  and  ultimately  after  constant  futile  move- 
ments, exhausting  itself.  If  one  cerebellar  lobe  is  removed,  the  body  when 
at  rest  is  curved  toward  the  side  of  the  lesion,  and  the  movements  of  the 

865 


866 


THE    CENTRAL    NERVOUS    SYSTEM 


animal  cause  it  to  fall  in  that  direction.  A  similar  experiment  with 
dogs  yields  like  results,  but  the  operation  is  of  course  considerably  more 
difficult.  In  man,  a  destructive  tumor  of  the  cerebellum  produces  a  con- 
dition known  as  "cerebellar  ataxy,"  in  which  the  patient  moves  his 
limbs  in  a  very  incoordinate  fashion;  he  staggers,  is  uncertain  in  his 
gait,  and  behaves  in  general  very  like  a  drunken  man. 

Although    these    immediate    effects    of    cerebellar    extirpation    indicate 


Fig.    222. — Footprints    after    destruction    of    the    cerebellum    in    a    dog:      a,    before    the    operation; 
b,  four  days  after;  c,  five  days  after;  d,  a  month  after;  e,  two  months  after.      (From  Luciani.) 


clearly  that  this  organ  has  to  do  with  the  control  of  muscular  movements, 
yet  the  results  are  probably  not  primarily  dependent  on  the  ablation, 
but  rather  on  the  conditions  of  irritation  which  are  set  up  as  a  result  of 
the  operation,  and  which  probably  affect  the  cerebellar  peduncles.  At 
least,  such  is  the  view  that  Lueiani,  one  of  the  greatest  investigators  in  this 
field,  has  adopted  because  of  the  fact  that,  if  the  animal  is  kept  alive  for 
sufficient  time  so  that  the  symptoms  of  irritation  disappear,  they  become 


FUNCTIONS    OK    THE    CEREBELLUM  867 

replaced  by  those  of  an  entirely  different  nature.  The  pigeon  may  reac- 
quire the  power  of  (lying  straight,  QV — and  this  is  particularly  important — 
the  dog  may  reacquire  the  power  of  apparently  normal  progression,  al- 
though, if  its  muscular  movements  are  carefully  examined  hy  physiologic 
methods,  it  will  he  found  that  al  least  three  changes  have  developed  as  a 
late  result  of  the  extirpation;  namely,  a  weakness  of  contraction,  a  tremor 
during  the  contraction,  and  a  want  of  tone  when  at  rest.  These  condi- 
tions have  been  called  asthenia,  atonia  and  astasia,  respectively.  On  su- 
perficial examination  it  may  often  be  difficult  to  make  out  these  three  con- 
ditions, but  they  can  readily  be  observed  in  animals  in  which  the  cerebellar 
extirpation  has  been  performed  on  one  side,  so  that  the  abnormal  may  be 
compared  with  the  normal  side.  In  a  dog  that  has  had  one  cerebellar 
hemisphere  removed  some  time  previously,  the  muscles  on  the  correspond- 
ing side  are  so  much  weaker  than  those  on  the  opposite  side  that  the 
animal,  in  order  to  retain  his  equilibrium,  has  to  prop  himself  up  either 
by  leaning  against  whatever  object  may  be  convenient,  or  by  extending 
his  legs  so  as  to  increase  his  base  of  support.  In  other  words,  he  constantly 
tends  to  fall  to  the  side  of  the  lesion,  but  tries  to  prevent  this  either  by 
increased  muscular  effort  or  by  taking  advantage  of  artificial  support. 
The  effect  which  this  weakening  has  on  his  gait  can  be  very  clearly  demon- 
strated by  comparing  the  footprints  produced  by  the  normal  with  those  of 
the  abnormal  side,  these  footprints  being  obtained  by  making  the  animal 
trot  along  a  piece  of  glazed  paper  blackened  with  a  carbon  deposit  as  in 
taking  tracings  (Fig.  222). 

Localization  of  Function  in  the  Cerebellum 

Although  these  facts  in  themselves  would  tend  to  indicate  a  certain  de- 
gree of  localization  of  function  in  the  cerebellum,  or  at  least  that  certain 
parts  of  the  cerebellar  cortex  have  to  do  with  certain  groups  of  muscles, 
yet  for  many  years  it  was  considered  that  the  cerebellum  did  not  show  in 
any  marked  degree  the  same  kind  of  localization  that  we  find  in  the  cere- 
bral cortex.  One  cause  for  the  backward  state  of  our  knowledge  concern- 
ing cerebellar  localization  is  that,  unlike  the  cerebrum,  its  cortex  is 
practically  inexcitable.  In  recent  years,  however,  on  account  partly  of 
anatomic  and  partly  of  experimental  and  clinical  work  a  high  degree  of 
localization  has  been  found  to  exist  in  the  cerebellum.  From  the  anatomic 
point  of  view  it  has  been  found  that  in  certain  groups  of  animals,  such  as 
the  ungulata,  the  postero-medial  lobule  of  the  cerebellum  is  very  large. 
whereas  the  lobuli  ansiformes  are  small.  In  another  group,  the  carnivora, 
the  opposite  obtains,  the  lobuli  ansiformes  being  greatly  developed  and  the 
postero-medial  lobule  quite  small. 


868 


THE    CENTRAL   NERVOUS    SYSTEM 


By  studying  these  developmental  differences  in  relationship  to  the  activi- 
ties of  the  muscular  system,  Bolk  suggested  that  movement  of  those  regions 
of  the  body  which  are  affected  by  muscle  groups  on  both  sides — for  example, 
the  head,  neck  or  trunk — would  be  represented  on  the  cerebellar  cortex  by 
an  unpaired  center — that  is,  a  center  occupying  a  middle  position — and  that 
this  would  be  capable  of  exercising  an  influence  equally  upon  the  muscles 
of  both  sides.  Movements  of  the  limbs  would  require  an  entirely  different 
type  of  coordination,  since  they  are  not  accustomed  to  act  together,  unless 
for  certain  movements,  as  walking.  Based  on  these  theoretic  considerations 
Bolk  found  a  definite  correspondence  to  exist  between  the  variations  in  the 
development  of  certain  cerebellar  lobules  and  the  functional  importance  of 
certain  muscle  groups,  and  the  general  conclusions  deducible  from  his  and 


Fig.  223. — Diagrams  to  represent  respectively  a  ventral  view  of  the  left  half  and  a  dorsal 
view  of  the  right  half  of  the  human  cerebellum  illustrating  the  scheme  of  subdivision  according 
to  Bolk.  (From  photographs  of  specimens  from  the  Anatomical  Museum,  Western  Reserve  Medical 
School.)      (From  Davidson  Black.; 


correlated  work  may  be  summed  up  as  follows  (cf.  Davidson  Black16)  :  The 
lobus  anterior  cerebelli  (see  Fig.  223)  contains  the  centers  for  the  coordi- 
nation of  the  muscle  groups  of  the  head  (eyes,  tongue,  muscles  of  mastica- 
tion, muscles  of  expression),  and  of  the  larynx  and  pharynx.  The  lobus  sim- 
plex contains  centers  for  the  coordination  of  the  muscles  of  the  neck.  The 
lobulus  medianus  posterior  contains  the  unpaired  centers  for  the  synergic 
movements  required  by  the  right  and  left  extremities  for  the  purposes 
of  progression.  On  the  other  hand  paired  centers  for  the  extremities — 
those  centers  that  have  to  do  with  the  independent  movements  of  each  limb 
of  the  same  side  of  the  body — are  located  in  the  lobuli  ansiformes  et  para- 
median! (crus  primum  and  crus  secundum).     The  centers  for  the  rest  of 


FUNCTIONS   OF    THE    CEREBELLUM 


869 


the  trunk  and  tail  region  are  located  in  the  remainder  of  the  cerebellum. 
These  conclusions  are  the  basis  of  the  accompanying  map  of  the  cerebellum. 
Basing  his  work  on  these  anatomic  conclusions,  Van  Rijnberk  has  studied 
the  effect  of  circumscribed  extirpation  of  certain  lobules  of  the  cerebellum 
on  the  muscular  control  of  the  different  parts  of  the  body,  with  the  following 
results.  Total  or  partial  extirpation  of  the  lobulus  simplex  produces  side  to 
side  oscillations  of  the  head,  indicating  the  removal  of  the  influences  of  the 
cerebellum  that  control  the  movements  of  the  muscles  of  the  neck.  Complete 
extirpation  of  the  crus  primum  of  the  lobuli  ansiformes  causes  as  an  imme- 
diate— irritative — effect  dynamic  disturbances  of  the  fore  limb  of  the  same 
side,  replaced  later  by  a  condition  of  atonia,  which  makes  the  limb  hang 
limp,  and  of  asthenia,  which  makes  it  feeble  in  its  movement  when  it 
is  excited  to  contract.     Extirpation  of  the  crus  secundum  has  a  similar 


Fig.  224. — Schema  of  the  parts  of  the  mammalian  cerebellum  spread  out  in  one  plane.  (After  Bolk 
by  Van  Rijnberk  from  Luiciani.  Op.  cit.)  On  the  right  side  of  the  figure  the  relation  of  the 
different  lobules  to  the  functional  development  of  the  musculature  is  indicated  according  to  the 
theory   of  Bolk  noted  in   the  text.      (From   Davidson  Black.) 

influence  on  the  muscles  of  the  hind  limb  of  the  corresponding  side.  Extir- 
pation of  both  crura  of  the  lobulus  ansiformis  causes  marked  asthenia  and 
atonia  in  both  fore  and  hind  limb  on  the  same  side  as  the  lesion.  A  char- 
acteristic disturbance  in  walking  develops  as  a  late  effect  of  this  extirpation. 
It  has  been  termed  the  "hen's  gait."  Extirpation  of  the  lobulus  para- 
medians causes  rotation  on  the  longitudinal  axis  of  the  body,  with  pleuro- 
thotonus  to  the  operated  side.     (Fig.  224.) 

Just  as  in  the  case  of  cerebral  localization,  so  in  cerebellar  we  find  that 
within  each  of  the  largest  centers  a  more  particular  localization  can  be  made 
out;  thus,  in  each  of  the  centers  for  the  upper  and  lower  extremities, 
there  is  a  definite  arrangement  of  subsidiary  centers  for  the  direction  of 
the  activities  of  antagonistic  muscle  groups  concerned  in  the  movements  of 
particular  joints.  It  must  be  remembered,  however,  that  in  all  these  cases 
no  real  paralysis  is  produced  by  extirpation,  but  only  a  want  of  coordina- 


B70  TTir.    CENTRAL   NERVOUS    SYSTEM 

tion  on  account  of  the  fact  that  the  sthenic,  tonic  and  static  impulses  re- 
quired for  muscular  harmony  are  not  properly  elaborated. 

After  some  time,  as  in  the  case  of  complete  cerebellar  extirpation,  the 
symptoms  gradually  disappear,  but  they  can  be  obtained  more  or  less  char- 
acteristically in  practically  all  animals,,  at  least  in  all  those  that  have  been 
investigated,  including  dogs  and  monkeys. 

It  will  be  of  interest  to  consider  for  a  moment  the  possible  causes  for  the 
ultimate  disappearance  of  the  symptoms  of  cerebellar  extirpation.  These 
are  either :  (1)  an  organic  compensation  by  the  uninjured  parts  of  the  cere- 
bellum, or  (2)  a  functional  compensation  by  the  voluntary  centers  of  the 
cerebrum.  Although  the  former  of  these  methods  of  compensation  may 
sometimes  develop  after  partial  destruction  of  the  cerebellar  cortex,  it  can 
not  of  course  explain  the  recovery  which  we  have  seen  to  occur  after  the 
entire  cerebellum  has  been  removed.  The  most  important  compensation  no 
doubt  is  effected  by  the  cerebrum,  as  the  following  observation  clearly  in- 
dicates. If  half  of  the  cerebellum  of  a  dog  is  destroyed,  and  the  animal 
kept  alive  until  the  symptoms  of  cerebellar  extirpation  have  entirely  dis- 
appeared, it  will  then  be  found,  if  the  cerebral  center  on  the  opposite  side 
is  removed,  that  the  symptoms  return  in  their  original  severity.  After  this 
second  operation  the  powers  of  standing  in  the  erect  position  and  of 
walking  are  permanently  lost. 

CLINICAL  OBSERVATIONS 

Application  of  these  laboratory  results  has  been  recently  made  in  the 
clinic,  the  most  important  contribution  having  come  from  the  clinic  of 
Barany.  who  for  his  work  was  awarded  the  Nobel  prize.  In  cases  of  abscess, 
cysts,  or  regional  agenesia,  it  is  now  possible  to  determine  the  exact  site  of  the 
lesion  in  the  cerebellum.  To  effect  this  localization,  it  has  been  necessary  to 
work  out  certain  clinical  tests.  The  most  important  of  these  is  called  the 
index  test.  This  is  described  by  Davidson  Black  as  follows :  "The  patient's 
eyes  being  closed,  he  is  asked  to  execute  a  simple  movement  in  a  given 
direction  with  one  of  his  extremities.  For  example,  the  forearm  being 
firmly  supported,  the  patient's  index  finger  is  extended  and  brought  into 
contact  with  that  of  the  observer:  the  patient  is  then  required  to  move  his 
finger  vertically  downward  and  then  to  return  it  to  its  previous  position. 
The  test  is  repeated  a  number  of  times,  both  in  the  vertical  and  in  the 
horizonal  direction,  and  if  any  tendency  toward  deviation  from  the  plane  of 
movement  be  present,  its  direction  is  noted.  By  slight  modification  of  the 
foregoing  procedure  it  is  possible  to  test  each  of  the  limb  segments  in  all 
positions  of  rotation,  pronation  or  supination." 

The  index  test  is  applied  (1)  without  previously  producing  nystagmus 


FUNCTIONS   OF   THE   CEREBELLUM 


871 


and  (2)  after  producing  artificial  nystagmus.  The  artificial  nystagmus  is 
produced  by  spinning  t  bo  patient  two  or  three  times,  and  consists  of  con- 
stant lateral  movements  of  the  eyeballs,  quick  in  the  direction  in  which  the 
artificial  movement  took  place,  and  slow  in  the  opposite  direction. 

In  a  normal  subject,  previous  to  spinning  the  index  test  shows  no  devia- 
tion, but  after  the  production  of  artificial  nystagmus  a  deviation  is  noted 
in  the  direction  corresponding  to  the  slow  jerk  of  the  nystagmus  (reaction 


Fig.    225. 


Fig.    226. 

Figs.  225  and  226  represent  respectively  the  inferolateral  and  the  posterior  aspect  of  the  human 
cerebellum  indicating  certain  cerebellar  localizations  according  to  Barany.  (After  Barany,  from 
Andr6-Thomas  et  Durupt.  Op.  cit.)  N.  VII,  Nervus  facialis;  N.  IX,  Nervus  Glossopharyngeal 
N.  XII,  Nervus  hypoglossus. 

The  signs  in  the  above  diagram  indicate  the  exact  localization  of  the  centers  for  the  tonus  of 
the  musculature  concerned  in  some  of  the  movements  of  the  right  arm  and  leg,  ®  marks  the 
center  for  downward  movements  of  the  arm;  X,  for  abduction  of  the  arm;  O,  adduction  of  the 
hand;  +  adduction  of  the  arm;  ±,  adduction  of  the  hip.  N.  V.  indicates  Nervus  trigeminus; 
N.  VI,  Nervus  abducens;  N.  VII,  Nervus  facialis;  N.  IX,  Nervus  glossopharyngeus;  N.  XII, 
Nervus    hypoglossus.      (From    Davidson    Black.) 

deviation).  When  a  cerebellar  lesion  exists,  the  index  test  performed  on 
a  patient  without  nystagmus  sometimes  causes  a  spontaneous  deviation  in 
the  segment  of  the  body  corresponding  to  the  position  of  the  lesion  on  the 
cerebellar  cortex,  but  more  frequently,  if  it  is  applied  after  the  production 


S72  THE    CENTRAL    NERVOUS    SYSTEM 

of  artificial  nystagmus,  the  reaction  deviation  in  that  segment  will  fail  to 
be  obtained.  The  exact  site  of  the  cerebellar  lesion  is  diagnosed  partly 
from  the  nature  and  direction  of  the  deviation  which  is  produced  and 
partly  from  the  segment  of  the  limb  in  which  it  occurs,  the  explanation 
for  the  disturbances  being  that  interference  with  the  cerebellar  control  of 
one  muscle  group  causes  the  antagonistic  muscular  groups  to  perform  their 
movements  in  an  exaggerated  manner,  so  that  the  segment  moves  too  much 
in  their  direction. 

Barany's  conclusions  so  far  may  be  summarized  as  follows: 

(1)  The  centers  for  the  extremities  are  located  on  the  cortex  of  the 
hemispheres  in  the  semilunar  (superior  and  inferior)  and  digastric  lobules 
(see  Fig.  225).  The  representation  is  uncrossed  or  homolateral,  thus  con- 
trasting with  cerebral  localization,  in  which  it  is  crossed  or  heterolateral. 

(2)  "Within  each  of  these  chief  centers  there  is  a  further  localization, 
which  however  does  not  refer  to  anatomic  groups  of  muscles  but  rather  to 
the  functional  performances  of  the  different  segments  of  the  limb.  Thus, 
within  the  arm  centers  there  are  subsidiary  centers  concerned  in  the 
movements  of  the  limb  in  the  various  planes  in  rotation,  in  pronation 
and  in  supination.    It  is  a  functional  rather  than  an  anatomic  localization. 

(3)  "vThen  a  center  concerned  in  the  movements  of  the  limb  in  a  certain 
direction,  e.  g.,  to  the  right,  is  suddenly  destroyed,  a  spontaneous  devia- 
tion is  produced  in  the  opposite  direction  (to  the  left) . 


CHAPTER  C 

THE  CEREBELLUM  AND  THE  SEMICIRCULAR  CANALS; 
FUNCTIONAL  TESTS 

The  cerebellum  serves  as  the  great  nerve  center  to  which  are  transmit- 
ted, through  the  various  proprioceptors,  the  impulses  which,  as  it  were, 
inform  it  as  to  the  exact  degree  of  muscular  effort  required  to  maintain 
the  animal  in  its  various  postures.  It  is,  as  Sherrington  puts  it,  the  head 
ganglion  of  the  proprioceptive  system.  Such  impulses  from  the  muscles, 
tendons,  etc.,  could  not,  however,  supply  information  regarding  the  exact 
position  of  the  hody  in  space.  For  this  purpose  special  receptors  con- 
nected with  the  eighth  nerve  are  provided  in  the  semicircular  canals. 
These,  it  will  he  remembered,  are  three  in  number  on  either  side,  each  canal 
consisting  of  a .  semicircular  bone  tube  attached  to  the  vestibule  of  the 
internal  ear;  and  they  are  arranged  so  that  they  lie  at  right  angles  to  one 
another  in  the  three  planes  of  space.  The  three  canals  on  either  side  are 
thus  disposed  so  as  to  form  an  arrangement  like  a  V-shaped  armchair  with 
the  back  inwards.  This  arrangement  causes  the  posterior  vertical  canal 
of  one  side  to  be  in  the  same  plane  as  the  superior  vertical  canal  of  the 
opposite  side,  the  external  canals  being  in  the  horizontal  plane  on  both 
sides.    The  arangement  will  be  plain  from  the  diagram  (Fig.  227). 

Within  the  osseous  canals  are  suspended  membranous  tubes,  which  do  not 
fill  the  canals.  The  canals,  etc.,  contain  fluid,  but  are  not  completely 
filled.  The  osseous  as  well  as  the  membranous  canals  are  dilated  at  one 
end  to  form  the  ampulla,  and  it  is  here  that  the  vestibular  division  of  the 
eighth  nerve  ends  in  a  structure  called  the  "crista  acustica,"  consisting  of 
hair  cells  supported  by  snstentaeular  cells.  The  nerve  terminates  in  fine 
arborizations  between  the  hair  cells.  In  the  saccule  and  utricle  are  struc- 
tures similar  to  the  crista,  called  the  macula1  acustica1.  These  structures  arc 
receptors  specialized  for  the  purpose  of  responding  to  changes  in  the 
position  of  the  head,  and  therefore  of  the  body  in  general.  When  the 
head  moves  in  a  certain  plane  of  space,  the  fluid  in  the  membranous  canals 
and  in  the  utricle  and  saccule  on  account  of  inertia  undergoes  a  certain 
movement,  which  acts  on  the  hairs  of  the  hair  cells  and  thus  sets  up  a 
stimulus.  According  to  the  degree  of  the  stimulation  in  the  various 
ampulla?,  which  again  will  be  dependent  upon  the  plane  or  planes  in 
which  the  movement  of  the  head  has  occurred,  impulses  are  transmitted 

873 


874 


THE    CENTRAL    NERVOUS    SYSTEM 


through  the  vestibular  nerve,   and  these   impulses  ultimately   reach  the 
cerebellum. 

The  experimental  evidence  for  these  conclusions  regarding  the  functions 
of  the  semicircular  canals  is  very  strong.  Thus,  after  destruction  of  all 
the  canals — an  operation  which  is  particularly  easy  in  the  pigeon — the 
animal  behaves  very  much  the  same  as  after  cerebellar  destruction.  After 
some  months  these  disorders  disappear,  because  the  cerebellum  learns  to 
control  the  movements  of  the  body  from  other  proprioceptive  impulses, 
particularly  those  of  sight.  If  such  a  recovered  animal  is  bandaged,  the 
symptoms  return  in  all  severity.  This  compensation  is  furthermore  an 
educative  process,  for  it  does  not  occur  when  the  cerebral  centers  as  well 


Fig.    227. — The   semicircular   canals    of    the    ear,    showing    their    arrangement    in    the    three    planes    of 
space.      (From   Howell's   Physiology.) 

as  the  semicircular  canals  are  removed,  and  it  can  be  abolished  in  a  re- 
covered animal  by  removal  of  the  cerebral  cortex. 

Many  observations  of  great  interest  have  been  made  concerning  these 
labyrinthine  sensations  by  Pike  and  others,  but  we  can  not  discuss  them 
further  here.  One  point  of  interest,  however,  is  that  forced  movements 
in  definite  planes  are  induced  by  removal  of  a  canal.  Removal  of  the 
horizontal  canals,  for  example,  causes  continued  nodding  movements  of 
the  head  in  the  plane  of  the  injured  canals.  An  experiment  of  great  sig- 
nificance was  performed  by  Ewald  to  show  the  effect  of  causing  a  move- 
ment of  the  fluid  in  one  of  the  canals.  For  this  purpose  a  bony  canal  was 
opened  at  two  places  by  a  dental  drill.  Through  the  hole  farther  from  the 
ampulla,  amalgam  was  introduced  so  as  to  block  the  backward  movement 
of  fluid,  and  into  that  nearer  the  ampulla  a  fine  tube  was  inserted  con- 
nected with  a  rubber  bulb.     By  manipulating  the  bulb,  the  membranous 


('Ki;i:r.i:i.U'.\i    \\i>   tim:  skmkircuLAK   CANALS  87.r) 

canal  could  be  compressed  and  currents  set  up  in  the  endolymph.  It  was 
found  that  these  currents  always  caused  the  animal  to  move  its  head  and 
eyes  in  the  plane  of  the  canal  that  was  being  stimulated  and  in  the  direction 
of  the  current  of  endolymph. 

Finally,  visual  impressions  supply  much  of  the  information  the  cerebel- 
lum requires,  the  close  association  of  the  movements  of  the  eyeballs  with 
cerebellar  and  labyrinthine  disturbances  being  well  recognized.  The  nys- 
tagmus already  described  in  connection  with  Barnay's  tests  is  dependent 
upon  this  association.  The  symptoms  and  sensations  of  giddiness  or  nausea 
produced  by  rotation  of  the  body,  or  by  unusual  movements  such  as  those 
of  a  boat,  are  no  doubt  due  to  the  irregular  and  unusual  variety  of  laby- 
rinthine sensations  which  they  excite. 

In  a  word,  then,  the  function  of  the  cerebellum  is  to  receive  proprio- 
ceptive impulses  from  the  body  along  with  labyrinthine  and  visual  im- 
pressions and  to  integrate  and  develop  from  them  impulses  which,  by 
being  transmitted  to  the  cerebral  and  other  nerve  centers  that  dominate 
muscular  movements,  so  coordinate  the  nerve  discharges  from  them  that, 
when  muscular  movement  occurs,  it  does  so  in  relationship  to  the  previous 
position  of  the  animal  and  in  the  most  efficient  way  to  attain  the  object 
for  which  the  movement  was  made.  The  cerebellum  is  the  head  nucleus 
of  the  proprioceptive  system. 

THE  ASSOCIATION  BETWEEN  THE  EYE  MOVEMENTS  AND  THE 
SEMICIRCULAR  CANALS 

The  close  association  between  the  eye  movements  and  the  semicircular 
canals  is  indicated  by  the  occurrence  of  nystagmus  when  the  ear  is  stimu- 
lated either  electrically  or  by  means  of  moderately  cold  water  impinging 
on  the  membrana  tympani.  The  latter  method  of  inducing  nystagmus  is 
styled  the  caloric,  and  is  employed  in  the  examination  of  candidates  for 
the  aviation  service.  Its  value  over  the  tests  of  nystagmus  after  rotating 
the  body  and  the  index  test  already  described  depends  on  the  fact 
that  it  enables  us  to  test  each  vestibular  apparatus  separately. 

Water  at  68°  F.  is  allowed  to  run  through  a  stop  nozzle  into  the  ex- 
ternal auditory  canal,  free  of  wax,  from  an  irrigation  bottle  placed 
about  3  feet  above  the  head,  which  is  meanwhile  tilted  at  an  angle  of  30° 
forward.  In  about  40  seconds  a  rotary  nystagmus  with  the  direction  of 
the  jerk  to  the  side  opposite  to  the  douched  ear  should  be  evident,  or 
dizziness  complained  of.  The  reaction  test  is  then  applied  and  im- 
mediately afterward  the  head  is  inclined  at  an  angle  of  60°  backward 
from  the  perpendicular,  when  a  horizontal  nystagmus  to  the  side  op- 
posite to  the  douched  ear  should  develop.     Deviation  is  again  tested. 


876  THE   CENTRAL   NERVOUS   SYSTEM 

The  procedure  is  repeated  on  the  oilier  ear.  If  it  takes  longer  than  00 
seconds  for  the  nystagmus  to  appear,  the  vestibular  apparatus  of  that 
side  is  abnormal.  Absence  of  the  reaction  deviation  after  the  douching  is 
a  certain  sign  of  internal  ear  disease. 

It  is  undoubtedly  essential  that  these  tests  should  be  most  carefully 
applied  to  all  would-be  aviators.  They  frequently  reveal  lesions  of  the 
vestibular  apparatus  or  the  cerebellum  in  subjects  who  had  thought 
themselves  perfectly  normal,  and  who  indeed  may  have  boasted  of  their 
powers  of  equilibrium  because  they  imagined  that  freedom  from  seasick- 
ness or  failure  to  become  dizzy  in  dancing  indicated  a  high  development 
of  this  function.  There  can  be  no  doubt  that  many  aviators  have  gone  to 
their  death  because  of  impairment  in  the  ear  mechanism.  When  on  "terra 
firma"  the  muscular  sense  and  cutaneous  sensations  often  make  the 
vestibular  weakness  of  no  consequence,  but  when  deprived  of  these  con- 
tributory sensations  and  dependent  on  the  ear-balance  mechanism  alone, 
as  in  flying,  any  weakness  becomes  a  serious  menace. 


CHAPTER  CI 

THE  AUTONOMIC  NERVOUS  SYSTEM 

In  discussing  the  physiology  of  the  central  nervous  system,  we  have 
broken  away  from  the  traditional  textbook  treatment  of  the  subject  in 
that  we  have  left  practically  untouched  any  description  of  the  course  of  the 
various  nerve  tracts  or  of  the  position  of  the  nerve  centers.  We  have 
pursued  this  policy  in  the  belief  that  the  study  of  these  details  of  structure 
belongs  just  as  surely  to  the  anatomist  as  does  the  structure  of  other  parts 
of  the  body,  notwithstanding  that  to  trace  the  course  of  the  nervous  path- 
ways he  may  have  to  call  to  his  aid  the  physiologist  and  clinical  neurologist. 
There  is  one  part  of  the  nervous  system,  however — namely,  the  involuntary 
or  autonomic — the  physiology  of  which  it  is  impossible  to  discuss  apart 
from  its  anatomy,  because  this  has  depended  very  largely  on  physiologic 
methods  for  its  elucidation.  Until  such  methods  were  emphasized  and 
while  anatomy  alone  was  depended  upon,  little  could  be  learned  of  the 
functions  and  connections  of  the  sympathetic  chain  and  of  the  various 
nerve  plexus  that  compose  the  involuntary  nervous  system.  We  shall  here 
review  briefly  the  general  anatomic  plan  of  this  system  as  described  by 
Gaskell.17 

GENERAL  PLAN  OF  CONSTRUCTION 

The  plan  of  the  involuntary  nervous  system  is  much  the  same  ;is  that 
of  the  voluntary,  the  main  points  of  difference  being  dependent  upon  the 
location  of  the  neurons  composing  the  reflex  arcs.  It  will  be  remembered 
that  there  are  three  of  these:  the  receptor,  the  internuncial,  and  the  ef- 
fector neurons  (page  782).  The  receptor  neurons  have  the  same  position 
for  both  systems;  namely,  the  posterior  root  ganglia  (Fig.  228).  The  inter- 
nuncial neurons  of  the  involuntary  system,  like  those  of  the  voluntary, 
have  their  cells  in  the  spinal  cord,  where  they  are  represented,  in  the 
thoracic  region,  by  the  cells  of  the  lateral  horn  of  gray  matter;  in  the 
sacral  region,  by  a  similarly  placed  collection  of  cells;  and  in  the  bulbar 
region,  mainly  by  the  dorsal  nucleus  of  the  vagus.  The  main  cause  for 
the  difference  between  the  two  systems  is  dependent  on  the  course  of  the 
fibers  of  the  internuncial  neurons ;  in  the  involuntary  system  they  leave  the 
spinal  cord  before  connecting  with  the  effector  neuron  nerve  cells,  which 
arc  contained  in  the  various  ganglia  found  throughout  the  body,  whereas 

877 


878 


THE    CENTRAL   NERVOUS   SYSTEM 


in  the  voluntary,  they  remain  within  the  spinal  cord,  and  terminate  on 
the  effector  neurons,  which  are  the  anterior  horn  cells. 

The  outflow  from  the  spinal  cord  of  involuntary  internuncial  fibers, 
which  we  shall  hereafter  style  connector  fibers,  occurs  along  the  an- 
terior spinal  roots,  but  is  somewhat  irregular  in  distribution,  because 
it  is  interrupted  in  the  cervical  and  lumbar  regions,  where  the  nerve 
plexus  for  the  extremities  come  in.  There  are,  therefore,  three  main 
regions  of  outflow  for  the  connector  fibers — a  thoracolumbar,  a  bulbar, 
and  a  sacral;  and  the  fibers  (Fig.  229)  do  not  behave  in  the  same  manner 
in  all  of  them.  The  fibers  of  the  thoracolumbar  region  form  the  so- 
called  sympathetic  system,  and  run  by  the  corresponding  white  rami 
communicantes   either  immediately  to  the   ganglia   of  the   sympathetic 


Post  root 
gang. 


Gray 
ramus 

Fig.  228. — Diagram  to  illustrate  the  different  arrangements  of  the  internuncial  neurons  of  the 
voluntary  and  involuntary  nervous  systems.  In  both  systems  the  afferent  fiber  terminates  (by  col- 
laterals) around  a  cell  of  the  gray  matter  of  the  cord.  In  the  voluntary  system  this  cell  is  sit- 
uated in  the  posterior  horn,  and  its  axon  travels  to  an  anterior  horn  cell.  In  the  involuntary 
system,  on  the  other  hand,  it  is  located  in  the  lateral  horn,  and  its  axon  leaves  the  cord  by  the 
anterior  root  and  travels  by  the  white  ramus  into  a  sympathetic  ganglion,  where  it  connects  with 
a  nerve   cell,   whose  axon   forms  the   postganglionic   fiber.      (From   Gaskell.) 


chain,  or  by  the  splanchnic  nerves  to  the  abdominal  ganglia.  In  the  gan- 
glia are  situated  the  cells  of  the  effector  neurons.  The  fibers  of  the  sacral 
region  connect  with  effector  neurons,  forming  the  pelvic  ganglionic  group 
(pelvic  nerves,  nervi  erigentes)  ;  and  those  of  the  bulbar  outflow  with 
effector  neurons  located  either  peripherally  or  in  the  ganglia  of  the 
vagus  and  the  seventh,  ninth,  and  eleventh  cranial  nerves.  In  the  mid- 
brain there  is  a  fourth  group  of  involuntary  connector  fibers  running  to 
effector  neurons  found  in  the  ciliary  ganglia. 

The  anterior  roots  of  many  of  the  spinal,  nerves  are  therefore  not 


Fig.  229. — Diagram  of  the  sympathetic  nervous  system  to  be  used  along  with  Fig.  23i.  The 
preganglionic  fibers  are  in  red,  and  the  postganglionic  in  black.  S.c,  superior  cervical  ganglion; 
I.e.,  inferior  cervical  ganglion;  T,  stellate  ganglion;  S.p.,  great  splanchnic  nerve;  C,  ganglia  of 
solar  plexus;  m.,  inferior  mesenteric  ganglia;  h.,  hypogastric  nerves;  N.E.,  nervus  erigens.  The 
arrows  indicate  the  direction  of  nerve  conduction.  The  numerals  indicate  the  spinal  nerves. 
(From   Howell.) 


-Spinal  cord 


) Sympathetic  chain 


:  ^*  1  ;---oolar  ganglion 


Fig.  230. — Diagram  (after  I.anglty)  showing  the  manner  of  connection  of  the  fibers  compos- 
ing the  great  splanchnic  nerve.  The  left-hand  diagram  represents  the  usual  arrangement,  the 
preganglionic  fibers  (black)  passing  through  the  ganglia  of  the  sympathetic  chain  and  having 
their  cell  stations  in  the  solar  ganglion,  from  which  the  postganglionic  fibers  (red)  then  emerge 
to  run  to  their  destination  along  the  blood  vessels.  The  right-hand  diagram  shows  a  possible 
exceptional    arrangement. 


THE   AUTONOMIC    NERVOUS   SYSTEM  879 

composed  entirely  of  fibers  belonging  to  voluntary  effector  neurons,  but 
also  of  connector  fibers  of  the  involuntary  system.  These  are  distin- 
guished from  the  voluntary  fibers  by  being  much  smaller  in  diameter; 
indeed  it  was  by  this  characteristic  that  Gaskell  succeeded  in  tracing  the 
course  of  the  involuntary  fibers. 

In  brief,  therefore,  the  fibers  of  the  internuncial  neurons  of  the  volun- 
tary nervous  system  are  confined  "within  the  central  nervous  system, 
where  they  are  contained  mainly  in  the  white  columns  of  the  spinal  cord,  the 
pyramidal  tracts,  for  example,  being  composed  of  internuncial  fibers 
from  the  cerebral  neurons;  the  corresponding  fibers  of  the  involuntary 
nervous  system  (connector),  on  the  other  hand,  run  out  of  the  cord  with 
the  anterior  roots  to  effector  neurons  situated  either  in  the  ganglia  of 
the  sympathetic  chain  or  in  peripheral  localities.  Just  as  the  voluntary 
internuncial  fibers  give  off  many  collaterals,  so  do  those  of  the  involun- 
tary system,  so  that  an  impulse  transmitted  by  one  internuncial  neuron 
may  excite  a  broad  field  of  effectors.  We  shall  see  later  that  it  is  through 
these  collaterals  that  reflex  responses  can  apparently  often  be  excited 
by  the  stimulation  of  the  central  ends  of  nerves — such  as  the  hypogastric 
to  the  bladder — after  all  connections  with  the  central  nervous  system 
have  been  severed.     (Fig.  230.) 

To  elucidate  the  further  course  of  the  involuntary  fibers,  and  deter- 
mine the  location  of  the  effector  neuron  nerve  cells,  it  becomes  necessary 
to  supplement  anatomic  with  physiologic  methods  of  investigation.  The 
various  functions  of  the  innervated  parts — vascular  changes,  muscular 
movements,  glandular  activity — are  observed  by  the  usual  methods  of 
the  physiologist,  and  the  nerve  roots  or  nerves  believed  to  contain  the 
involuntary  fibers  either  cut  or  stimulated.  If  a  change  is  observed  in 
the  functions,  it  indicates  that  part  at  least  of  the  involuntary  nerve 
supply  is  contained  in  the  nerve  structure  that  has  been  cut  or  stimu- 
lated. Such  a  result  does  not,  however,  inform  us  as  to  whether  the 
fiber  is  that  of  the  connector  or  effector  neuron — whether  it  is  pre- 
ganglionic or  postganglionic.  This  may  be  determined  in  many  cases 
by  observing  whether  nerve  degeneration  occurs  as  a  result  of  cutting 
the  fibers,  but  the  most  useful  method  for  answering  the  question  is 
that  discovered  by  Langley  by  the  use  of  nicotine,  which  in  certain  con- 
centrations specifically  paralyzes  the  synaptic  connections  between  the 
connector  and  the  effector  neurons.  If  a  weak  (1  per  cent)  solution  of 
this  alkaloid  is  painted  on  a  ganglion  or  peripheral  nerve  plexus  in 
which  the  connector  neuron  finds  its  effector  nerve-cell,  it  will  break 
the  nerve  path,  so  that  physiologic  responses  produced  by  stimulating 
the  preganglionic  fibers  become  no  longer  elicitable.  When  the  involun- 
tary connector  fibers  run  through  several  ganglia,  as  in  the  sympathetic 


880  THE    CENTRAL   NERVOUS    SYSTEM 

chain,  it  becomes  possible,  by  systematically  painting  the  ganglia  with 
nicotine,  to  tell  exactly  in  -which  of  them  the  fiber  finds  its  effector 
nerve  cell. 

The  course  and  functions  of  the  effector  neurons  of  the  three  outflows — 
bulbar,  thoracicolumbar,  and  sacral — vary  in  many  details  and  must  be 
considered  separately. 

THE  THORACICOLUMBAR  OUTFLOW,  OR  SYMPATHETIC 
SYSTEM  PROPER 

The  connector  fibers  are  sharply  confined  in  their  outfloAv  from  the 
cord  between  the  first  thoracic  and  the  fourth  lumbar  segments,  and 
they  run  by  the  white  rami  communicantes  to  the  sympathetic  chain, 
where  some  of  them  connect  with  effector  nerve  cells  in  its  ganglia,  while 
others  run  beyond  the  chain  to  find  their  effector  cells  in  collateral  gan- 
glia represented  by  the  semilunar,  superior  and  inferior  mesenteric  and 
the  renal  in  the  abdomen.  The  fibers  of  the  effector  cells,  often  called 
postganglionic,  are  distinguished  from  the  connector  or  preganglionic 
fibers  by  being  nonmedullated.  Those  derived  from  cells  in  the  lateral 
sympathetic  ganglia  proceed  to  their  destination  either  by  way  of  the 
gray  rami  communicantes  to  the  segmental  nerves  after  the  fusion  of 
the  anterior  and  posterior  spinal  roots,  or  by  the  outer  walls  of  the  blood 
vessels.     (Fig.  231.) 

The  effector  neurons  supply  the  following  structures: 

1.  The  blood  vessels  and  heart. 

2.  The  musculature  of  the  sweat  glands. 

3.  The  musculature  of  the  hair  follicles  and  other  muscles  lying  under 
the  skin. 

4.  The  musculature  of  the  so-called  segmental  duct,  which  is  repre- 
sented in  the  adult  by  the  uterus,  Fallopian  tubes,  ureters,  etc. 

5.  The  sphincters  of  the  intestine. 

Eegarding  the  innervation  of  the  Mood  vessels,  the  exact  situation  of 
the  ganglia  in  which  the  effector  neurons  are  situated  and  of  the  nerve 
roots  which  contain  the  connector  fibers,  is  shown  in  the  accompanying 
table  (page  881). 

It  is  clear  that  the  innervation  of  the  blood  vessels  is  practically  con- 
tinuous, the  effector  neurons  being  situated  both  in  the  lateral  and  in  the 
collateral  chain  of  ganglia.  Those  of  the  former  run  to  the  vessels  of 
structures  innervated  by  the  cranial  and  spinal  segmental  nerves,  while 
those  of  the  latter  supply  the  vessels  of  the  abdominal  and  pelvic  viscera. 

The  connector  fibers  to  the  sweat  (/lands  are  also  strictly  confined  to 
the  thoracicolumbar  system,  the  cell  station  being  found  in  the  ganglion 


Post.  roof- 
Ant,  roof- - 


i Preganglionic  fiber 


\ — Sympathetic  ganglion 


White  rami 


--'—--Postganglionic  fiber 


Fig.  231. — Diagram  (after  T.angley)  to  show  the  manner  in  which  a  preganglionic  fiber, 
emanating  from  the  spinal  nerve  by  the  white  ramus  communicans,  connects  in  a  ganglion  of  the 
sympathetic  chain  with  a  nerve  cell  (red),  the  axon  of  which  then  proceeds  as  the  postganglionic 
filler  (red)  by  way  of  the  gray  ramus  communicans  back  to  the  spinal  nerve,  along  which  it 
travels  to  the  periphery.  It  will  lie  observed  that  the  preganglionic  fiber  does  not  form  its 
synapsis   in   the   first  ganglion   it  encounters. 


THE   AUTONOMIC    NERVOUS   SYSTEM  881 

stellatum  for  the   fore  limb,  and  the  lower  lumbal-  and  upper  sacral 
ganglia  for  the  hind  limb.     When  they  are  stimulated,  the  muscular 

li hers  surround i lit;-  the  sweat  glands  contract  and  squeeze  out  the  sweat. 

SITUATION  OF  BLOOD  SITUATION    OF   MOTOR  BOOTS  CONTAINING  CONNECTOR 

VESSELS  GANGLION  CELLS  NERVES 

Head  and  neck.  Superior  cervical  ganglion.  1,  2,  3,  4,  5,  thoracic;  2,  3,  4,  give 

maximum  effect. 

Heart.  Ganglion   stellatum   and   in-       1,  2,  3,  4,  5,  thoracic;   2,  3,  give 

ferior  cervical  ganglion.  maximum. 

Anterior  extremity.       Ganglion  stellatum.  4,  5,   6,   7,  8,  9,  thoracic,  and  10 

slightly. 

Posterior  extremity.     Gth  lumbar,  7th  lumbar,  and       11,   12,   13,   thoracic;   1,  2,  lumbar 
1st  sacral  ganglion.  and  3  slightly. 

Kidney.  Renal  ganglion.  4,    5,    0,    7,    8,    9,    10,    11,    12,    13, 

thoracic:    1,  2,   3,  4,  lumbar. 

Spleen.  Semilunar  ganglion.  3,  4,  5,  6,  7,  8,  9,  10,  11,  12,  13, 

thoracic;   1,  2,  3,  lumbar. 

Abdominal  viscera.       Superior  mesenteric  ganglion       6,  7,  8,  9,  10,  11,  13,  thoracic;  1,  2, 
and  semilunar  ganglion.  3,  lumbar. 

Pelvic  viscera.  Inferior  mesenteric  ganglion.       1,  2,  3,  4,  lumbar. 

(Gaskell) 

The  ganglia  for  the  pilomotor  fibers  are  more  widespread  (extending 
from  the  fourth  thoracic  to  the  coccygeal  ganglia) ;  but  the  connector 
fibers  are  again  strictly  confined  to  the  thoracicolumbar  region.  Stimu- 
lation of  these  fibers  causes  movement  of  the  hairs,  or  on  hairless  animals, 
the  condition  called  "goose  skin." 

The  Motor  Nerves  of  the  Muscles  Surrounding  the  Segmental  Duct. — 
It  will  be  observed  that  the  connector  fibers  to  the  abdominal  and  pel- 
vic viscera  are  collected  into  two  special  nerve  trunks,  the  greater  and 
the  lesser  '(or  lumbar)  splanchnics.  The  collateral  ganglia  (semilunar 
and  superior  and  inferior  mesenteries)  with  which  these  connect,  have 
nothing  to  do  with  the  segmental  nerves,  but  their  nerve  cells  send  fibers 
(postganglionic)  which  supply  the  various  viscera  not  only  with  vaso- 
motor fibers  but  also  with  the  "sympathetic"  fibers,  which  we  have  seen 
exercise  such  an  important  control  over  their  glandular  and  muscular 
functions. 

All  of  the  fibers  contained  in  the  lumbar  splanchnics  do  not,  however, 
have  their  cell  stations  in  the  inferior  mesenteric  ganglia,  but  run 
through  it  and  proceed  in  the  hypogastric  nerves  to  find  their  effector 
cells  on  the  musculature  of  the  various  structures  that  are  developed 
from  the  Mullerian  and  Wolffian  ducts — i.  e.,  of  the  ureters,  uterus,  Fal- 


882  THE  CENTRAL  NERVOUS  SYSTEM 

lopian  tubes  and  vas  deferens.  Many  of  the  fibers  of  the  hypogastric 
nerves  are  therefore  those  of  involuntary  internuncial  neurons. 

The  ileocolic  and  internal  anal  sphincter  muscles  of  the  intestines  and 
internal  vesical  sphincter  receive  their  nerve  supply  from  effector  neurons 
situated  in  the  superior  and  inferior  mesenteric  ganglia,  the  internuncial 
fibers  arising  from  the  thoracicolumbar  region.  It  is  possible  that  the 
other  sphincters  of  the  intestinal  canal — viz.,  the  cardiac  and  pyloric 
sphincters  of  the  stomach — are  similarly  innervated.     (Fig.  232.) 

Great  aid  in  working  out  these  nerve  connections  is  received  by  study- 
ing the  effect  of  epinephrine,  which  acts  specifically  on  those  tissues  that 
are  supplied  by  the  sympathetic  nervous  system.*  Epinephrine  has  no 
effect  on  tissues  innervated  by  the  bulbar  or  sacral  outflows,  and  it 
develops  its  action  peripherally,  being  indeed  more  potent  on  a  dener- 
vated  organ  even  after  all  its  nerves  have  been  allowed  to  degenerate. 
Advantage  of  this  action  of  epinephrine  has  been  taken  in  the  investi- 
gation of  doubtful  cases  of  sympathetic  innervation,  such  as  in  the  cere- 
bral, coronary,  and  pulmonary  blood  vessels.  The  outcome  of  these  in- 
vestigations has  been  discussed  elsewhere. 

THE  BULBOSACRAL  OUTFLOW  OR  THE  PARASYMPATHETIC 

SYSTEM 

From  the  medulla  oblongata  arise  involuntary  connector  neurons, 
which  are  carried  mainly  by  the  vagus  nerves  but  partly  by  the  seventh, 
ninth  and  eleventh  cranial  nerves  to  effector  nerve  cells  situated  periph- 
erally on  the  structures  to  which  the  nerves  run  (Fig.  233).  These  include 
in  a  general  way  the  muscles  and  glands  of  the  alimentary  canal  and 
its  derivatives  as  far  as  the  end  of  the  small  intestine.  In  the  small 
intestine  itself  the  cells  of  these  motor  neurons  are  those  of  Auerbach's 
plexus  found  between  the  two  muscular  coats.  In  the  diverticula,  which 
include  the  lungs  and  the  gall  bladder,  the  nerve  cells  to  which  the 
vagus  fibers  run  are  also  situated  peripherally. 

The  sacral  outflow  occurs  through  the  second  and  third  sacral  nerves, 
the  fibers  joining  to  form  a  single  nerve  (the  pelvic  nerve  or  nervus 
erigens)  on  each  side.  This  passes  directly  to  the  bladder,  where  it 
connects  with  a  plexus,  often  called  the  hypogastric,  which  extends  over 
the  bladder  and  neighboring  portion  of  the  rectum.  The  branches  run 
to  connect  either  with  the  nerve  cells  of  the  ganglia  of  the  plexus  itself, 
or  with  nerve  cells  situated  on  the  walls  of  the  large  intestine  and  blad- 
der.    The  pelvic  nerve  makes  its  connections  with  the  periphery  in  the 


*Its  action   is  always  the  same  as  that  which  is  produced   hy  stimulation  of  the  sympathetic  nerve 
supply,  whether  this  effect  is  one  ot   stimulation   or  inhibition. 


iTj^Medulla 
C. 


=  Key  — 

PreGangiionic  Sympathetic 
PostGanglionic  Sympathetic 
Pre  Ganglionic  Bulbo-Sacral 

(Parasympathetic) 
PostGanglionicBulbo-Sacral 


Arm 
Post 
9«n9J 


Head  & 
__  Neck 

(Pregang.) 

Sympathetic 
Ganglia 

Thoracic 
6planctinic 
nerve 


Arm 
f (Pregang) 


Coeliac  Plexus  & 
5yp.Me5.Qang. 


Leg 

( Pregang.}  , 


>Abdominal 

Viscera 

(Pregang.) 


Lumbar 
Splanchnic  nerve 


;JL  —  Inf.  Mes.Gang. 


yASp.  int. 
Pelvic  visceral  nerve 


Fig  232— Diagram  showing  the  main  parts  of  the  autonomic  nervous  system  to  be  used  along 
with  Fig.  233.  For  the  sake  of  clarity  several  of  the  preganglionic  fibers  of  the  sympathetic 
autonomics  are  omitted,  but  the  position  of  their  egress  from  the  cord  is  indicated  in  the  side 
notes.  The  diagram  shows  clearly  the  distribution  of  the  bulbosacral  autonomic  system  by  waj 
of  the  vagus  and  the  first,  second  and  third  sacral  nerves. 


THE    AUTONOMIC    NERVOUS   SYSTEM  883 

same  manner  as  the  vagus.  Taken  together  these  two  nerves  supply  the 
musculature  of  the  gastrointestinal  tract,  including  the  cloaca,  the 
vagus  as  far  as  the  end  of  the  small  intestine,  and  the  pelvic  nerve 
from  this  point  on.  It  must  of  course  be  remembered  that  certain 
muscles — namely,  the  sphincters  of  the  small  and  large  intestine — 
receive  their  nerve  supply  from  the  sympathetic  (page  882).  Just  as 
structures  innervated  by  the  sympathetic  are  peculiarly  susceptible  to 
the  action  of  epinephrine,  it  has  been  discovered  that  those  innervated 
by  the  bulbosaeral  system  are  very  susceptible  to  the  action  of  acetyl- 
choline, which  is  present  in  ergot.  They  are  not  acted  on  by  epinephrine, 
nor  are  the  structures  upon  which  this  acts  affected  by  acetyl-choline. 

AXON  REFLEXES 

At  this  place  it  is  convenient  to  consider  for  a  moment  the  phenome- 
non Avhich  has  already  been  referred  to  as  an  axon  reflex.  It  was  dis- 
covered that  when  one  of  the  hypogastric  nerves  was  cut  and  the  central 
end  stimulated  there  was  a  reflex  contraction  of  the  bladder  and  the  in- 
ternal anal  sphincter,  along  with  vasoconstriction  in  the  region  of  the  rec- 
tum and  that  this  occurred,  even  after  disconnecting  the  inferior  mesen- 
teric ganglion  from  the  spinal  cord  by  cutting  the  lumbar  splanchnic  nerves. 
Injection  of  nicotine  immediately  abolished  the  response.  It  looked  as 
if  reflex  action  was  possible  through  the  ganglion;  which  would  justify 
the  name  "sympathetic"  originally  given  to  the  involuntary  nervous  sys- 
tem in  the  belief  that  the  ganglia  were  centers  for  local  reflex  actions. 
Further  investigation  showed,  however,  that  this  reflex  is  not  similar  to 
those  occurring  in  the  voluntary  system,  but  is  dependent  upon  the 
presence  of  a  collateral  on  internuncial  fibers  that  run  through  the  in- 
ferior mesenteric  ganglia  to  nerve  cells  situated  peripherally  on  the 
walls  of  the  bladder  and  rectum.  The  collaterals  terminate  by  synapsis 
around  nerve  cells  in  the  ganglion,  the  axons  of  which,  as  we  have  seen, 
run  to  the  bladder,  the  rectal  blood  vessels,  and  the  internal  sphincter 
ani.  The  evidence  for  this  explanation  depends  on  the  observation  that 
the  axon  reflex  is  no  longer  possible  after  the  lumbar  splanchnics  have 
been  cut  and  time  allowed  for  their  fibers  to  become  completely  degen- 
erated. 

Similar  reflexes  depending  on  collaterals  have  been  found  in  the  lateral 
chain,  and  there  can  be  little  doubt  that  they  are  of  frequent  occurrence 
throughout  the  whole  involuntary  nervous  system,  just  as  they  are, 
within  the  spinal  cord,  in  the  voluntary.  It  is  because  of  these  collaterals 
and  the  fact  that  nerve  fibers  transmit  impulses  in  both  directions 
that  a  stimulus  transmitted  through  one  or  a  limited  number  of  connector 


884  THE    CENTRAL   NERVOUS    SYSTEM 

neurons  may  excite  a  broad  field  of  effectors  and  cause  a  widespread 
effect. 

FUNCTIONS  OF  AUTONOMIC  NERVES 

The  functions  of  the  autonomic  nerve  fibers  have  been  discussed  in 
connection  with  the  structures  which  they  supply,  and  we  shall  require  in 
this  place  only  to  review  them  in  a  general  way. 

Two  opposed  effects  may  be  obtained:  stimulatory  (augmehtory)  and 
inhibitory;  and  these  may  be  produced  through  one  nerve  by  its  being 
stimulatory  for  one  set  of  muscle  fibers  and  inhibitory  for  another  set 
in  the  same  viscus.  The  branches  running  from  the  inferior  mesenteric 
ganglion  to  the  colon,  for  example,  are  augmentory  (constrictor)  for  the 
blood  vessels  and  inhibitory  for  the  muscular  Avails  of  the  colon. 

The  greatest  interest  centers  on  the  inhibitory  impulses.  They  are 
best  known  in  connection  with  the  vagus  nerve  to  the  heart,  the  sympa- 
thetic to  the  small  intestine,  and  the  hypogastric  to  the  musculature  of 
the  bladder.  It  is  interesting  to  compare  the  nature  of  inhibition  in  the 
involuntary  and  voluntary  systems.  In  the  latter,  it  will  be  remembered, 
inhibition  can  occur  only  through  the  internuncial  neurons  and  the  ef- 
fector nerve  cell,  stimulation  of  the  effector  nerve  fiber  never  having 
any  other  than  an  augmentor  effect.  It  is  quite  otherwise  in  the  involun- 
tary nervous  system,  for  stimulation  of  the  effector  nerve  fiber,  after 
complete  destruction  of  the  effector  nerve  cell,  is  still  followed  by  a  typical 
inhibition.  This,  it  Avill  be  remembered,  may  be  demonstrated  on  the  frog 
heart  by  applying  electric  stimulation  to  the  white  crescentic  line  after 
paralyzing  the  effector  nerve  cells  by  nicotine.  The  same  may  also  be 
shown  in  the  case  of  the  chorda  tympani,  where,  stimulation  of  the  post- 
ganglionic fibers  in  the  hilus  of  the  gland  causes  dilatation  of  the  blood 
vessels  after  paralysis  of  the  ganglion  by  nicotine,  vasodilatation  being 
of  course  a  phenomenon  of  inhibition. 

It  is  a  difficult  matter  to  designate  precisely  which  fibers  in  any  part 
of  the  involuntary  nervous  system  are  inhibitory  and  which  augmentory. 
Indeed,  as  mentioned  above,  one  fiber  may  perform  both  functions.  In 
cases  where  the  existence  of  inhibitory  fibers  is  doubtful,  great  aid  is 
afforded  by  the  use  of  ergotoxine,  an  alkaloid  of  ergot,  which  possesses 
the  remarkable  property  of  specifically  paralyzing  Hie  augmentor  nerves 
of  the  sympathetic  system  (but  not  of  the  parasympathetic) ;  that  is, 
the  same  fibers  as  are  stimulated  by  epinephrine.  When  a  particular 
structure  is  supplied  with  augmentory  and  inhibitory  fibers  by  a  com- 
bined sympathetic  nerve,  electric  stimulation  or  the  application  of  epi- 
nephrine usually  gives  only  augmentory  effects;  after  the  injection  of 


Pilo  motor  ,nuscle 


Lachrymal_c[land 


-^Ciliary  gang       *~s^  gang. 

Nasal  mucosa 

Spheno-palaFgang. 
Sublinguals,-—^   Parotid  gland- 
gland    r  j 


Submaxillary  glan 

Submaxillary(Sublingual) 
ganglion 


Cranial  and  Sacral  nerves 
motor  =  red 
inhibitory  =  blue 

Thoraclco-lumbar  nerves 


Postganglionic  fibers 
are  dotted, thus— - 


N.XI 

Sup.  cervical  ganglion 


Thyroid  gland 


Infxervical  ganglion 
T-Ansa  subclavia 

-SteJIate  (i*J  Thoracic) 
ganglion 

Sweat  gland 


lliocecal 
sphincter 

Bladder 

Vesical  sphincter 

Urethral  sphincter 


^-Vasomotor 
fibers 

Pilo  motor  muscle 


Celiac  (Semilunar) 

ganglion(Solarplex) 
Splanchnic  nerves 

^^Sympathetic  chain 


Lumbar  splanchnics 

Sup.  Mesenteric 

ganglion 


Inf.  Mesenteric 
ganglion 

hypogastric  nerves 


Pelvic(HypogastricJnterUidc) 
plexus.  {Vesicals,  rectal  portions)      Pelvic'nerves  {Nervus  erigens) 

7?    P  HailecK 


Fig.    23i. — Schematic    representation    of    the    involuntary    nervous    system.      (From   Jackson.) 


THE    AUTONOMIC    NERVOUS   SYSTEM  88") 

ergotoxine,  however,  a  reversed  effed  is  observed;  namely,  inhibition 
instead  of  augmentation.  By  taking  advantage  of  this  fact,  Dale  1ms 
been  able  to  demonstrate  in  the  hypogastric  nerves  inhibitory  fibers  to 
the  uterus,  and  Elliotl  lias  demonstrated  the  inhibitory  action  of  epi- 
nephrine on  the  muscles  of  the  ureter  in  the  dog.  Inhibitory  fibers  have 
also  been  discovered  by  these  methods  in  the  great  splanchnic  nerves,  in 
the  nerve  routs  supplying  the  kidney,  and  in  the  cervical  sympathetic 
supplying  the  blood  vessels  of  the  mucous  membrane  of  the  mouth,  etc.; 
that  is,  in  nerve  trunks  which  previously  were  believed  to  contain  only 
augmentory  fibers.  The  accompanying  diagram  from  Jackson  will  give 
an  idea  of  the  currently  accepted  views  concerning  the  distribution  of 
augmentory  and  inhibitory  fibers.     (Fig.  233.) 

THE  AFFERENT  FIBERS  OF  THE  AUTONOMIC  SYSTEM 

It  has  long  been  known  that  the  exposed  viscera  are  remarkably  insen- 
sitive. This  experience  is  in  accord  with  the  observation  that  the  supply 
of  afferent  fibers  to  the  viscera  is  relatively  very  small.  In  the  hypo- 
gastric and  probably  in  the  great  splanchnic  nerve,  Larrgley  computes 
that  only  about  one-tenth  of  the  medullated  fibers  are  afferent.  At  the 
two  ends  of  the  alimentary  canal,  where  cooperative  reflexes  between 
the  somatic  musculature  and  the  viscera  are  of  importance,  a  greater 
number  of  afferent  fibers  are  found  in  the  autonomic  nerves;  for  ex- 
ample, in  the  pelvic  nerve  about  one-third  of  the  fibers  are  afferent,  and, 
as  we  have  frequently  seen,  the  vagi  contain  large  numbers  of  them 
coming  from  the  lungs,  stomach,  and  no  doubt  from  other  viscera. 

The  afferent  visceral  fibers,  as  above  stated,  arise  like  those  of  the 
voluntary  system,  from  the  ganglion  cells  of  the  posterior  roots.  They 
travel  in  company  with  the  connector  fibers  through  the  white  ramus 
communicans,  so  that  the  stimulation  of  the  central  end  of  one  of  these 
may  cause  reflex  rise  in  blood  pressure  and  other  movements. 

It  is  found  that,  after  opening  the  abdominal  cavity  under  local 
anesthesia,  cutting  and  suturing  of  the  viscera  may  be  continued  without 
causing  any  pain.  When  the  viscera  are  inflamed,  however,  and  under 
certain  conditions  of  stimulation,  such  as  the  distention  of  the  bile  ducts 
with  biliary  calculi,  or  the  violent  contraction  of  the  intestines,  excruci- 
ating pain  may  be  evoked.  This  pain  is  frequently  not  localized  in  the 
viscera,  but  is  referred  to  certain  parts  of  the  surface  of  the  body,  and 
it  has  been  shown  by  Mackenzie  and  by  Head  that  it  is  referred  to  the 
area  of  skin  which  is  supplied  with  sensory  nerves  by  the  same  segment 
as  that  to  which  the  afferent  autonomic  fibers  of  the  particular  viscus 
run.     It  has  further  been  shown  that  vascular  disease  may  cause  sensi- 


886  THE    CENTRAL   NERVOUS   SYSTEM 

tivity  of  the  corresponding  cutaneous  areas,  so  that  clinical  methods  are 
available  for  localizing  the  site  of  the  disease  by  studying  the  exact 
position  and  extent  of  the  referred  pain  or  skin  tenderness. 

NERVOUS  SYSTEM  REFERENCES 
(Monographs  and  Original  Papers) 

iParker,  G.  H. :     Proc.  Am.  Philos.  Soc,  1911,  i,  217-225. 
-'Head,  H.,  and  Elvers,  W.  H.  R.:     Brain,  1908,  xxxi,  323-450. 
3Meek,  W.  J.:     Am.  Jour.  Physiol.,  1911,  xxviii,  356-360. 
*Bruce,  A.  Ninian:     Arch.  f.  exper.  Path.  u.  Pharmakol.r  1910,  lxiii,  426-433. 
^Sherrington,    C.    S. :      Numerous    papers   on    reciprocal    innervation    of    antagonistic 
muscles,  Proc.  Roy.  Soc,  Vol.  B,  66;  also  in  Jour.  Physiol.,  xxii,  xxxiv,  xxxviii, 
xliii,  and  Quart.  Jour.  Exper.  Physiol.,  ii. 
5Holmes,  Gordon:     Brit.  Med.  Jour.,  1915,  ii,  Nov.  27,  Dec.  4  and  11. 
ePike,  F.  H. :     Am.  Jour.  Physiol.,  1909,  xxiv,  124-152. 
TJolly,  W.  A.:     Quart.  Jour.  Exper.  Physiol.,  1910,  iv,  67-87. 
"Lombard,  W.  P.:     Jour.  Physiol.,  ]889,  x,  122-148. 
sCollier,  J.:     Lancet,  April  1,'  1916,  711. 
loRanson,  S.  W.,  and  von  Hess,  C.  L.:     Am.  Jour.  Physiol.,  1915,  xxxviii,  128. 
nHead,  H.,  and  Thompson:     Brain,  1906,  xxLx,  537. 
"Sherrington,  C.  S.,  and  Brown,  T.  Graham:     Jour.  Physiol.,  1913,  xlvi,  Proc.  Physiol. 

Soc,  p.  xxii. 
"Brown,  T.  Graham,  and  Sherrington,  C.  S. :     Proc  Roy.  Soc,  1912,  85,  B-,  250-277. 
14Cushing,  Harvey:     Proc.  Am.  Physiol.  Soc,  Am.  Jour.  Physiol.,  1909. 
15Luciani,  L. :     EHeinhirn,  Ergebnisse  der  Physiol.,  1904,  i. 
"Black,  Davidson:     Cerebellar  Localization  in  the  Light  of  Recent  Research,  Jour.  Lab. 

and  Clin.  Med.,  1916,  i,  467. 
"Gaskell,  W.  H. :     The  Involuntary  Xervous  System,  Monographs  on  Phvsiologv,  ed.  by 
E.  H.  Starling,  Longmans,  Green  &  Co.,'  1916. 

Other  Monographs  not  Specifically  Referred  to  in  the  Context 

"Sherrington,  C.  S. :  (1)  The  Integrative  Action  of  the  Xervous  System,  Silliman  Lec- 
tures, Yale  University.  Scribner's  Sons,  New  York.  (2)  Shafer's  Textbook  of 
Physiology,  II.     Young  J.  Pentland,  London,  1899. 

"Bolton,  J.  S.:  Recent  Researches  en  Cortical  Localization  and  on  The  Function  of 
the  Cerebrum  in  Further  Advances  in  Physiology,  ed.  bv  Leonard  Hill,  London, 
E.  Arnold,  1909. 


INDEX 


Abdominal   respiration,   307 
Abnormal   pulses,   276 
Absorption,   in   general,   13 

from  stomach,  456 

of  fats,  691 
Acapnia,  292 

Accessory  food  factors,  584 
Acetaldehyde,  708 
Acetoacetic    acid,    683,    709 
Acetone,    683,    709 
Acid : 

buffer   action,   36 

excretion  of,  by  kidneys,  46 

number    of    fats,    687 

total   concentration  of,   32 
Acidity,  actual  degree   of,   23 
Acidosis : 

ammonia-urea  ratio   during,   616 

compensated,   39 

in    diabetes,    683 

in  nephritis,   683 

in  starvation,  569 

relationship  to  alveolar  C(X,  354 

relationship  to  breathing,  354 

theory  of,  38 

uncompensated,   39 
Acids,  of  urine,  524 
Actual  degree  of  acidity  and  alkalinity, 
Adenine,  635 
Adenosine,   638 
Adjusters,    783 

Adrenal  glands  and  diabetes,  673 
Adrenaline    (see   Epinephrine) 
Adsorption,  65 

compounds,    70 

conditions   influenced  by,   67 

effect  of  chemical  forces  on,  68 

effect  of  electric  changes  on,  67 

everyday  reactions  depending  on,   66 

of  gases,  66 
Afferent  fibers  of  autonomic  system,  88c 
Afferent  spinal  pathways,  830 
Age,   584 

effect  on  creatinine  excretion,  624 
Alanine,  600,  603,  606,  649,  666 
Albolene  absorption,   692 
Albuminuria,  519 

Alkali  retention,  determination  of,  48 
Alkaline  buffer,  36 
Alkaline  reserve,  38 

measurement   of,  41 


23 


Allantoin,  636,  639,  645 
Allied    reflexes,    simultaneous    integration 
of,  823 
successive  integration  of,  823 
Alloxan,  635 
Alveolar  air: 

clinical  investigation  of,  347 
estimation  of  gases  in,  344 
Fridericia  method,  340 
Haldane  method,  340 
Pearce  method,  345 
tension  of  CO,,  46,  339,  356 

during    breathing    in    confined    space, 
357 
tension  of  oxygen,  339 
Ambard's  equation,   527 
in  acid  excretion,  48 
Amboceptor,   96 
Amino  acids,  597 

and  energy  output,  541 
in  blood,  606 
chemistry  of,  598 
determination  of,  599 
fate  of,  610 
groups,   598 
in  growth,  576 
in  tissues,  607 
in  urine,  530,  620 
structure  of,  602,   603 
Aminoacetic  acid   (see  Glycocoll) 
Aminopropionic  acid    (see  Alanine) 
Ammonia : 

ammonia-urea  ratio: 

influence   of  acidosis  on,  616 
in   disease,   620 
influence  of  liver  on,  617 
as  reserve  alkali,  616 
excretion  of,  615 

excretion  of  acid  in  combination  with,  46 
of  urine,  530 
Ammonium  carbamate,  616 
Ammonium  carbonate,  616 
Amoeba,  782 
Amylases,  81,  90,  491 
Amylolysis,  491 

in  stomach,  454 
Amylopsin,   491,   656 
Anacrotic  wave,  pulse,  203 
Analysis    (psychic),   858 
Anaphylactic  reaction,  595,  601 
Anaphylaxis,  89 
Anarthria,   862 
Anastomosis,  intestinal,  470 


887 


S.S8 


INDEX 


Anemia,  93 

bloodflow  in,   283 
Anesthesia,  831 
Aneurism,  bloodflow  in,  28-4 

pulse  in,  143,  200 
Angina  pectoris,  fibrillation  in,  196 
Animal   calorimeter,    536 
Anions,  16,  59 
Antagonistic  muscles,  818 
Antagonistic  reflexes,  824 
Anterior  roots,  787 
Anticoagulants,  99 
Antidromic  impulses,  234 
Antiferments  in  blood,  89 
Antithrombin,  104,   112 
Antitoxins,   69 
Antitrypsin,  90 

Aortic  regurgitation,  pulse  in,   131 
Apesthesia,   838,   851 
Apex  beat,  tracing  of,  275 
Aphasia,  motor,  860,  862 

sensory,  862 

subcortical,  862 
Apnea,  nervous  element  in,  332,  362,  365 
Apparatus   for   measuring   respiratory    ex- 
change,  554 
Appetite  juice,  nature   of,  440 
Are,  reflex.   78  - 
Arginase,   81,  616 
Arginine,  605,  616,  627 
Aromatic  sulphates,   632 
Arrhythmia  of  sinus,  266,  277 
Arterial  pressure,  122 
Arteries,  bloodflow  in,  198 
Arteriosclerosis,   diastolic   pressure   in,    143 
Aspartie  acid,  605,  666 
Asphyxia,  311 
Assimilation  limit,   652 

dation  areas,  cerebral,  852,  861 

neurons,  783,  785 
Astasia,  cerebellar,  8C7 
Asthenia,  867 

Asthma,  dead  space  in,  311 
Ataxy,    cerebellar,    866 
Atonia,  cerebellar,  867 
Atophan,  651 

Atropine,  effect  on  glands,  422 
Auditory   center,    851 
Auricle,  pressure  in,  148 

propagation  of  beat   in,   191 
Auricular  curve,  contour  of,  153 
Auricular  fibrillation,  196,  269,  280 
Auricular  flutter,  196,  269,  279 
Aurieuloventricular  orifice,   148 

bundle,   183 

node,  183 
Ausculatorv   method    (of   blood   pressure), 

130 
Autoeatalysis,    77 
Autonomic  nerves,  cerebral,  423 

sympathetic,  423 
Autonomic  nervous  system,   >77 
afferent  fibers  of.  885 


Autonomic  uervous  system    -Cont'd 

axon  reflexes  in,  883 

bulbosacral  outflow,  882 

connector  fibers  of,  878 

functions  of,  884 

general  plan  of   construction,  878 

parasympathetic,   882 

thoracicolumbar   outflow,   880 
internal   vesical   sphincter,    882 
Axon,  784 

reflexes,  797,  883 
Azelaie   acid,   712 

B 

Bacillus  eoli  communis,  500 
Bacteria,  in  intestine,  499,  057 

in  stomach,  482 
Bacterial  digestion,  499 
Balance,   energy,  535 

material,  543 

sheet  of  body,  543 
Banting   cure,   571 
Basal  heat  production,  538 
Basal  ration,  576 
Basophile  cells,  96 
"Bends"  in  caisson  workers,  402 
Benzoic  acid,  630,  710 
Benzoyl   chloride,   631 
Beriberi,    584 

Beta-hvdroxy  butvrie  acid,  709 
Bile,  4*42 

and  fat  digestion,  690 

chemistry  of,   494 

constituents  of,  492 

from  gall  bladder,  492 

functions   of,  493 

pigments  of,  495 

salts,  494 
Bilirubin,  495 
Biliverdin,  495 
B-imidazolylethylamine,     effect     on     blood 

vessels,   397 
Birds,  removal  of  liver  from,  618 
Blood: 

absorption  into,  13 

amino  acids  in,  606 

amount  in  body,   135 

antiferments  of,  89 

circulation  of,  122 

dissociation   curve   of,   383 

fat  of, 

estimation,  696,  697 
variations  in,  697 

ferments  of,  89 

gases  of,  transportation,  379 

general  properties  of,  85 

mass  movement  of,  281 

means  by  which  gases  are  carried,  390 

oxidation  in,  396 

proteases  of,  89 

proteins  of,   87 
origin,   88 


INDI'X 


889 


II] I      Gont  M 

quantity  of,  in  bodj ,  B5 
refractive  index  of,  88 
Bpeciflc  gravity  of,  s,; 

BUgar   level    of,   657 

regulation,  67] 
transfusion  of,  93,   135,   139 

viscosity  of,  140 

volume  of,  136 
water  content  of,  86 
Blood  cell,  red,  fate  of,  93 
origin  of,  92 
regeneration  of,  03 
bI  roma  of,  01 
white,  06 
Blood  clotting,  08 
in   diseases,   111 
in  physiologic  conditions,  110 
influence  of  calcium  on,  103 
influence  of  tissues  on,  104 
intravascular,  107 
methods  of  retarding,  in  drawn  blood, 

00 
negative  phase  of,  108 
theories  of,  106 
time  of,  100,   108 
visible   changes  during,  98 
Blood  corpuscles  in  mountain  sickness,  401 
Bloodflow: 

clinical  conditions  affecting  anemia,  283 
cardiovascular  diseases,  284 
fever,   284 

diseases  of  nervous  system,  285 
mass  movement  of,  208 
movement  in  veins,  214 
variations  in,  282 
velocity  of,  206 
visceral,  212 
Blood  gas  manometer,  381 
Blood  platelets,  07 
Blood  pressure,  122 
diastolic,  127 

effect  of  hemorrhage  on,  135 
effect  of  pleural  pressure  on,  306 
factors  maintaining,  134 
H-ion  of  blood  on,  237 
mean  arterial,  123 
in  shock,  200 
systolic,  127 
tracing,  125 
Blood  vessels,  880 

elasticity   of,   142 
tone  of,  236 
Body  fluids,  reactions  of,  35 
Body   weight   and   energy  production,   530 
Botulism,  503 
Bowman,  capsule  of,  507 
Bradycardia,  103 
Brain : 

circulation  in,  247 
vasomotor  nerves,  252 
volume  of,  250 


Breathing,  in  compressed  air,  399 
in  rarefied  air,  360 

periodic,  303,  371,  376 
Brownian  movement,  colloids,  r. 7 
Bruits,    158 

I '.ii  (Tor  action  of  blood,  374 
Buffer  substances,  36 
Building  stones   of   protein,   507 
Bulbosacral  outflow,  882 
Butyric  acid,  700 


C 


Cadavcrine,  629 
Caffeine,  635 
Caisson   disease,   402 
cause   of,   403 

decompression  of  workers,  406 
prevention,   404 
symptoms,  402 
working   conditions   in,   408 
Calcium  ion,  influence  on  clotting,  10.", 

influence  on  heart,  166 
Calcium  rigor,  166 
Calomel  electrode,    30 
Calorie,  535 
Calorimeter,  535 
animal,  536 
Benedict,  537 
bomb,  537 
hand,  281 
respiration,  536 
Eussel-Sage,  537 
Calorimetry,  direct,  546 

indirect,  546,  554 
Canals,   semicircular,    873 

removal   of,    874 
Cannabin,  577 

Capillary  analysis  of  colloids,  56 
Carbamino  reaction,   590 
Carbohydrates,  absorption  of,   057 
assimilation  limits,  652 
digestion  of,  656 
and  growth,  583 
metabolism  of,  652 
production  from  protein,   665 
saturation  limit,   652 
Carbon  balance,  547 
Carbon  dioxide,  combining  power,   42 
effect  on  respiratory  center,  352 
estimation  in  blood,  390 
output,   550 

volume  percentage  in  blood,   301 
Carbon  dioxide  tension,  337 

in  alveolar  air,  after  exercise,   367 
estimation  of,  339,  344 
in   mountain   sickness,   361 
in  periodic  breathing,   375 
in  arterial  blood,  337 
in   venous   blood,   342 
Carbonic  acid   {see  Carbon  dioxide) 
Carboxyl  group,  598 
Cardiac   decompensation,   311 


890 


INDEX 


Cardiac  depressor  nerve,  239 

Cardiac  muscle,  physiologic  characteristics 

of,  176 
Cardiac   pouch    (stomach),  453 
Cardiac   sphincter,   448 
Cardiorenal  disease,  bloodflow  in,  284 

energy  output  in,  542 
Cardiograms,   275 

Cardiovascular  disease,  bloodflow  in,  284 
Casein,  488,  576 
Caseinogen,  488 
Catalase,  90 
Cations,  16 
Catalysts,  72 
Catalytic  power,  23 
Celenterates,  nervous  system  of,  782 
Cellulose,   digestion  of,   500 
Centers : 

association,   852,   855 

diabetic,   672 

motor,   843 

sense, 

auditory,  851 
visual,  851 

sensory,   850 

word  centers,  862 
Cephalin,  689 
Cereals  and  growth,  581 
Cerebellar  ataxy,  866 
Cerebellum : 

ablation  of,  869 

clinical   observations,  870 

extirpation  of,  869 

functions  of,  865 

lobes  of,  868 

localization  of  function  of,  867 
Cerebral  circulation,  247 
Cerebral  compression,  253 
Cerebral  cortex,  stimulation  of,  844 

structure   of,   852 
Cerebral  localization,   843 

clinical  observations,   849 

hemispheres,  removal  of,  840 
Cerebral  vessels,  ligation  of,  247 
Cerebrospinal  fluid,   248 
Cerebrum,  higher  functions  of,  860 
Ch,  method  of  expressing,  27 
Cheyne-Stokes  breathing,  371,  377 
Chlorides,  urine,  513 
Cholesterol,  494,   688 

estimation  of,  697 
Choline,  689 

Chorda  tympani,  231,  396,  423 
Chromatolysis,   801 
Chromatine,    638 
Chromosones,  638 
Chyme,  456,  482 
Circle  of  Willis,  247 
Circulation  of  blood : 

control  of,  216 

influence  of  gravity  on,  244 

mass  movement  of  blood,  208 

through  the  heart,  257 


Circulation  of  blood — Cont'd 

through  the  liver,  255 

through  the  lungs,  253 

time  of,  213 
Circulation  time,  206 
Clinical  application,   circulation,  259 
nervous  system,  828,  849,  862 
respiration,  310,   399 
Clotting  of  blood   (see  Blood  clotting) 
Coagulative   ferments,   82 
Cod-liver  oil,  nutritive  value,  706 
Coefficient  of  oxidation,  393 
Coefficient  of  solubility  of  gases,  337 
Cold  spots,   792 
Collaterals,  784 
Colloids  : 

Brownian   movement,    57 

capillary   analysis,    56 

characteristic  properties  of,  50 

diffusibility   of,   51 

dispersion  means,  54 

dispersoid,  54 

electric  properties  of,   ~>~> 
osmotic   pressure,   57 

electrophoresis,   56 

external  phase,  54 

gelatinization,  61 

heterogeneous,   51 

homogeneous,   51 

imbibition,  62 

internal  phase,  54 

isoelectric  point,   64 

lyophobe,    60 

mutual   precipitation   of   colloids,    56 

osmotic  pressure  of,  141 

size  of  colloid  particles,  53 

suspensions,   53 

suspensoids    and    emulsoids,    action    of 
electrolytes   on,   63 

Tyndall  phenomenon,  51 
Compensated  acidoses,  39 
Complemental  air,  300 
Compressed  air  sickness,  399 

cause   of  symptoms,   403 
prevention  of,  404 
treatment    of,   406 
Concentration  cell,  30 
Concentration  point,  auricles,  185 
Conception,   861 
Concept,  861 

Conditioned  reflexes,  481,  856 
Conductivity,   determination   of,   17 

equivalent,  19 

molecular,  19 

specific,   17 
Conductivity  cell,   18 
Conglutin,  538 

Construction    of    autonomic    nervous    sys- 
tem, 877 
Contracture,  extension,   806 
Cooking,  593 

Coronary   circulation,    257 
Coronary  vessels,  vasomotor  nerves,  268 


INDEX 


Mil 


<  lorpora  quadrigemina,  840 
Bection  behind,  840 

set  ion  in  front  of,  840 
Corpuscles  of  blood,  red,  91 

white,   96 
Cortex,  removal  of,  843 
Coughing,  300,  412 
Cranial  cavity,  pressure  in,  ~:>1 
Creatine,  606,  613 

chemistry  of,  622 

estimation  of,  623 

in  disease,  626 

metabolism  of,  624 

origin  of,  626 
Creatinine,  613 

chemistry  of,  622 

coefficient,   624 

estimation,   623 

in  urine,  529 

metabolism,  624 

of  blood  in  disease,  651 

origin  of,  626 
Crista  acustica,  873 
Critical  concentration,  8 
Crossed  extension  reflex,  804 
Cuorin,  689 

Current  of  action  of  heart,  187 
Cyanosis,  360,  400 
( 'vsteine,  603 
Cystine,  577,  592,  604 
Cystosine,   637 
Cytases,  463 


D 


Dalmatian  dog,  purine  metabolism  of,  646 

Dalton  's  law,  336 

Dead  space,  302,   310 

Deafness,  864 

Deamidization,  deaminization,  501 

Deaminizing  enzyne,  639 

Decerebrate  rigidity,   808 

Decerebration,  843 

Decolorization   of   liquids   by   charcoal,   66 

Decompression,   406 

Defecation,  470 

blood  pressure  during,  412 
Defibrinated  blood,   101 
Degeneration,    successive,    813 
Deglutition,  445 
Delayed   conduction,   270,   276 
Delirium  cordis,  195 
Dendrites,   784 
Depression  of  freezing  point,  10 

of  urine,  523 
Depressor  nerve,  238,  239,  240 
Depressor   substances,   397 
Dessert,  physiologic  value  of,  437 
Detoxication  compounds,  629 
Detoxication  process,  501 
Dextrins,  491,  656 
Dextrose  (see  Glucose) 


Diabetes: 

acidosis  in,  684 

and  the  ductless   glands,  678 

assimilation  limits  in,  652 

blood  examination  in,  659 

blood  fat  in,  699 

center,  diabetic,  672 

early  diagnoses  of,  652 

energy  output  in,  542 

experimental,  672 

fat  metabolism  in,  683 

ketosis,  683 

pancreatic,  678 

nervous,  in  man,  674 
permanent,  676 
phlorhizin,  665 

postprandial   hyperglycemia,   659 
renal,  661 

starvation  treatment  in,  684 
treatment  of,  653 
Diabetic  acidosis,  684 
Diabetic  center,  672 
Diabetic  gangrene,  258 
Dialurie  acid,  645 
Dialysate,  52 
Dialysis,   12 

method,  colloids,  51 
Diaphragm,  action  of,  320,  321 

physiology   of,  324 
Diastolic  rilling  of  heart,  153 
Diastolic  pressure,  127,  132 

measurement  of,  in  man,  128 
Dicrotic  notch,  202 

wave,  203 
Diet  at  different  ages,  590 

of  different  communities,  589 
Dietetics,  588 

Differential  manometer,  381 
Diffusion,    12 

Digestibility  of  foods,  593 
Digestion,  by  pancreatic  juice,  489 
in  intestine,  489 
in  stomach,  481 
mechanism  of,  444 
Digestive  glands : 
control   of, 
hormone,  425 
nervous,  423 
general  physiology  of,  418 
microscopic    changes    during    activitv, 
418 
Dispersion  medium,  colloids,  54 
Dispersoid,  colloids,  54 
Dissociation,  16,  17 
Dissociation  constant,   19,   388 
Dissociation   curve : 
of  blood,  383 
of  hemoglobin,  383 

influence  of  salts  on,  385 

influence  of  H-ion  concentration  on, 

386 
influence  of  temperature  on,  386 
Dissociation  hypothesis,  applications  of,  21 
Dissociation,  rate  of,  380 


892 


INDEX 


Diuresis,  578 
Diuretics,   578 
Diver's  palsy,  402 
Douglas  method,  544,  558 
Dropped  beat,  271 
Du  Bois  formula,  541 
Ductless  glands,  729 
in   diabetes,   678 
Dyspnea,  314,  349 
Dystrophy,   isolation,   808 

E 

Earth  worm,  nervous  system  of,  783 

Eck  fistula,  617 

Eclampsia,  620 

Edema,  62,  120 

Edestin  and  growth,  577 

Effectors,   782 

Elastin,  digestion  of,  486 

Electric  conductivity,  16 

Electric  currents,  development  of,  29 

Electric  properties  of  colloids,  55 

Electrocardiograms,  158,  259 

normal,  261 

standardization  of,  260 

ventricular   complex,   262 

waves  of,  261 
P-wave,  189,  261 
T-wave,  220,  263 
Electrocardiograph,   260 
Electrocution,  cause  of  death  in,  195 
Electrolytes,  16 

action  of,  on  colloids,  63 
Electrolytic  solution  pressure,  29 
Electrophoresis   of   colloids,   56 
Electrostatic  attraction,   29 
Emboli,  107 
Emetics,  450 

Emotional  glycosuria,  675 
Emphysema,  311,  314,  324 
Empyema,  324 
Emulsions,  688 
Emulsoids,  colloids,  60 
Endocrine  organs,  729 
Endoenzyme,  71 
Endogenous  metabolism,   615 

of  purines,  647 
Energy  balance,  535 
Energy  output,  and  age,  541 
and  body  weight,  549 
and  disease,  542 
and  muscular  work,  549 
and  sex,  541 
and  surface  area,  540 
in  starvation,  568 
Enterokinase,  443,  489 
Enzymes,  71 

action  of  temperature  on,  74 

amylases,  81 

and  catalysis,  72 

antienzymes,  81 

nrginaso,   81 


Enzymes — Cont'd 

coagulative  ferments,  82 

conditions  of  activity,  82 

endoenzymes,  71 

glyoxylase,   82 

invertases,  81 

lipases,  81 

nature  of,  72 

oxidases,  82 

peculiarities  of,  80 

peroxidases,  82 

properties  of,  73 

proteases,  80 

reversibility  of  action  of,  25,  77 

specific  action  of,  73 

types  of,  79 

urease,  82 

velocity  constant,  74 
Epicritic  receptors,  790 
Epilepsy,   Jacksonian,    849 
Epinephrine,  236,  502 

and  diabetes,  673 
Equilibrium,  nitrogen,  571 
Equivalent,  conductivity,  19 
Erepsin,  490,  601 
Ergastoplasm,  420 
Ergot,  502 
Ergotoxine,  209 
Erythrocytes,  91 

fate  of,  94 

regeneration  of,  93 
Escapement,  218 
Esophagus,   during  SAvallowing,  446 

inhibition  of,  447 

peristaltic  wave  in,  447 
Esters,  686 
Ester  value,  687 
Ethereal  sulphates,   501,   632 
Excelsin,  577 

Exogenous  metabolism,  615 
Exophthalmic  goiter,  756 

energy  output  in,  542 
Excretion  of  acid  combined  with  ammonia, 

46 
Excretion  of  urine,  507 
Extension  contracture,   45,   806 
Extensor  thrust,  57 

reflex,  805 
Exteroceptors,  788,  822 
Extrasystole,   266 
Eyes,  movements  of,  847 


F 

Factor  safety,  in  diet,  592 
Fatigue  of  reflexes,  825 
Fats: 

absorption  of,  691 
chemical  theory,  693 
mechanistic  theory,  692 
and  growth,  583 
blood,  696,  697 

destination  of,  699 


[NDEX 


s!i:; 


Fats,  blood— Conl  M 
determination,  696 

during  absorption,  698 

during  fasting,  698 

variations  in,   697 
cliiiuistrv   of,  686 
depot  fat,  699,  700 

destination  of,  701 

, ^saturation    of,    705,    712 

digestion  of,  690 

Cat   dust,  696 

liver  fat,  699,  701 

metabolism  of,  696 

tissue  fat,  699,  706 

transportation   to   liver,   702 
Fatty  acids,  686 

acid  number,  687 

breakdown  of,   709 

ester  value,  687 

formation    from    carbohydrates,     701, 

707 
in  liver  in  disease,  703 
iodine  value,  688 
melting  point,   687 
Eeichert-Meissl  value,   688 
saponification  value,  687 
Feces,  499,  521 
Ferments   (sec  Enzymes) 
Ferments   in   blood,    89 
Fever,  bloodflow  in,  284 

cold-bath  treatment,  284 

purine  excretion   during,  648 
Fibers,  anterior  root,  100 

connector,  193 

internuncial,  802 
Fibrillation,  auricular,  196,  269 

ventricular,  195 
Fibrin,  99 

fibrin  needles,  99 

source  of,  101 
Fibrin  ferment   (see  Thrombin),  102 
Fibrinogen,  87,  101,  103,  111 
Filtration,  13 

Final  common  path,  787,  821,  824 
Fistula,  biliary,  492 

gastric,  434 

salivary,  430 
Flexion-reflex,  804,  821 
Flutter,  auricular,  269 
Food: 

accessory  factors  of,  593 

cooking,   importance   of,   593 

effect  of,  on  circulation,  243 

effect  on  creatinine  excretion,  624 

laxative  qualities,  594 

palatability,  593 
Food  factors,  accessory,  584 
Foodstuffs,  rate  of  leaving  stomach,  458 
Forced  breathing,  324 
Formaldehyde  titration,  amino  acids,  487 
Formation  of  solid  surface  films,  66 
Freezing  point  constant,  10 
Freezing  point,  depression  of,  10 


Fridericia's  method   Cor  alveolar  air,  340 

Frontal  visual  center,  851 

Fructose,  666 

Functions  of  autonomic  nerves,  884 

Fundus  of  stomach,  452 


G 


Gallstones,  -191 

Galvanometer,  string,    187,  259 

Ganglia,  784 

Gas  in  stomach,  462 

Gas  laws,  3,  336 

Gases,  adsorption  of,  66 

coefficient   of   solubility,   337 

estimation  of,  344 

partial  pressure  of,  336 

solution  of,  336 

tension  of,  336 

transportation  in  blood,  390 
Gaskell's   clamp,   17.1 
Gastric   contents,    regurgitation    of,    449 
Gastric  digestion,  481 

rate  of,  487 
Gastric  fistula,  434 
Gastric  juice,  quantity  secreted,  440 

strength    of,    441 
Gastric   secretion,    4.r;2 

hormone   control   of,   437 
local  stimulation  of,  438 
nervous  control  of,  434 
Gastric  tube,  453 
Gastrin,    439,    456 
Gastroenterostomy,   460 
Gastrointestinal  contents,  reaction  of,  505 
Gelatin,   578 
Gelatinization,  61 
Glands,   changes   during   activity,   422 

electric  changes,  422 

normal   conditions   of   activity,   430 

oxygen   consumption    of,   S96,   421 

respiration  of,  396 
Globulin,    577 
Gliadin,  576 
Glomerulus,    507 
Gluconeogenesis,  662,  677,  680 

direct   method,   663 

indirect    method,    664 

in  normal  animals,  667 
Glucose,   708 

fate   of  absorbed,   662 

glucose  to  nitrogen  ratio,  664 

injections,   intravenous,   653 
subcutaneous,    656 

parenteral   assimilation,    656 

tolerance  for,  653 

utilization  of,  in  tissues,  677 
Glutamic  acid   (see  Glutaminic  acid) 
Glutaminie  acid,   605,   667 
Glutein,   577 
Glutelin,  577 
Glyceric  aldehyde,  665 
Glycerol,  665 


-U4 


INDEX 


Glvcocholic  acid,  494,  631 
Glycine,  494,  603 
Glvcinin,    577 

Glycocoll,  601,  630,  667,   710 
Glycogen,  662 

fate   of,   669 

sources    of,    662 
Glycogenase,  662 
Glycogenolysis,   669 

hormone,    676 

nervous,   672 

postmortem,    670 
Glycolaldehyde,   665 
Glycolysis,   677 

Glyconeogenesis    (see   Gluconeogenesis) 
Glycosuria,  alimentary,  659 

emotional.    675 

postprandial,   659 

relation  to  sugar  of  blood,  660 

renal,  661 
Glvcuronates,   630 
GlVcuronic   acid,   630,   631,   632 
Glyoxal,  631 
Glyoxylase,   82,   666 
Glvoxvlic    acid.   631 
G-X-ratio,   664 
Goiter,  exophthalmic.   542 
Gout,    648,    650 

etiology  of,  ' 

guanine,  640 

uric   acid   excretion   in,   648 
Grading  of  intensity  of  reflex  action,  809 
Gram    molecule,    3,    5 
Gram    molecular    solution,    22 
Gravity,    on    circulation,    244 

compensation   for,    245 
Growth,  574 

accessory   factors,    585 

basal  ration,  576 

carbohydrates  and,  583 

curves    of,    576 

curves  of  inhibition,  579 

fats  and,  583 

inorganic  salts  and,  586 

lysine  and,  578 

proteins  and.   574 

trypanophane  and,   578 

vitamines,    584 
Guanidine,  605,   622 
Guanine,  635 

gout,  640 
Guanosine,  638,  639 
Giinsberg  reagent,  487 


H 


Haldane-Barcroft  apparatus,   45 
Haldane  gas  apparatus,  559 
Haldane's  method  for  alveolar  air,  340 
Heart : 

action   of,   144 

auricular   curve,   153 

diastole  of,  145 


Heart— Cont  M 

isometric  period  in,   149 

muscle,   properties,   176 

nutrition     of,  161 

opening  and  closing  of  valves,   154 

oxygen  requirements  of,  396 

oxygen   supply  of,   164 

perfusion  of  outside  body,  161 

postsphygmic    period,    150 

presphygmic  period,  149 

pressure   in,   146 

pumping  action  of,  134,  144 

resuscitation  in  situ,  164 

rhythmic   power  in,   170,   174 

sounds  of,  157 

systole  of,  145 

utilization   of   glucose   in,   681 

vagus   control   of,   cold   blooded,   217 

vagus  control  of,  mammalian,  220 

vagus   terminations    in,   225 

ventricular  curve.  146 

work  of,  212 
Heart    beat : 

arrhythmia   of,  266 

myogenic  hypothesis   of,   171 

neurogenic   hypothesis    of,    170,    172 

origin   of,   in   cold-blooded   animals,   170 

origin  of,  in  mammalian,  182,  189 

pace  maker  of.  174 

propagation   of,   224 

sympathetic   control   of,   223,    227 

ultimum    moriens,    185 

vagus  control  of,  217.  220 
Heart  block,  174.  270.  276 

effect  of  vagus  on,  219 
Heart  disease,  vital  capacitv  of  lungs  in, 

314 
Heartdung   preparation,   158 
Heat   production  and   age   and  sex,   541 
and  body  weight,   539 
surface,  540 
disease,  542 
Heat  spots,  792 
Heat  value  of  foods,  535 
Hematocrit,  7 
Hematoporphyrin,  496 
Hemiplegia,   258 
Hemodromograph,    200 
Hemoglobin,   91 

dissociation  constant,  388 

dissociation,   curve    of,    380,    382,   383 

estimation  of,   92 

rate  of  dissociation,  386 

relationship  to  bile  pigments,  496 

specific  oxygen  capacity  of,  379 

transportation   of   O,   by,   390 
Hemolysis,  7,  95 
Hemolytic  jaundice,  93 
Hemophilia,   112 

Hemopoietic  activities  of  bone  marrow,  93 
Hemorrhage,   59 

immediate  effects  of,  137 

recovery  from,  138 


I  MH    \ 


895 


Hemorrhagic  diseases,   1 12 
Henle,  loop  of,  "|||7 
Eepatic  artery,  flow  in,  255 
Heterocyclic  t'ompounds,  604 

1 1  excises,    652 

Hibernating  animal,  metabolism  of,  549 
Hibernation,  breathing  during,  .".74 
Higher  functions  of  cerebrum,  860 
H  ion  or  hydrogen  ion,  168 
II  Lon    concentration,   22 
after  hemorrhage,   142 
catalytic  power  of,  23 
determination   of,   31 
of  intestinal   contents,   505 
law  of  mass  action  and,  26 
method  of  expressing,  27 
method   of   measurement : 
electric   method,    29 
indicator   method,   32 
standard  solutions  for,   34 
H-ion    concentration    in    blood: 

effect   on   dissociation   curve,   386,   389 
effect  on  respiratory  center,  335 
Hippuric  acid,  530,  630,  710 
Hirudin,    100 
Histamine,   397,    502 
Histidine,    606,    623 
Homogcntisic  acid,  502,  531 
Hordein,  578 
Hormones,  3,  729 

in  control  of  circulation,  216 
respiratory,  349 
Howell  .  theory    (blood    clotting),    106 
Hunger,   471 
Hunger   contractions : 

alcoholic    beverages    and,    478 
control    of,   476 
during    starvation,    475 
in  esophagus,  474 
inhibition  of,  477 
in  stomach,  471 
nerve  centers  and,  479 
remote  effects   of,   474 
rhythmic,  471 
splanchnic  nerve   and,   477 
vagus  nerve  and,  477 
Hiirthle   manometer,   1 26,   146 
Hydrocephalus,    249,    253 
Hydrochloric  acid,   amount   of,   482 
and   emptying   of   stomach,    460 
functions  of,  482 
source   of,   483 
Hydrogen  ion  (see  H  ion) 
Hyperacidity,  461 
Hyperesthesia,  831 

Hyperglycemia,     in     pancreatic     diabetes, 
680 
postprandial,   659 
splanchnic,   673 
Hyperpnea,  349,  359 
Hyperthyroidism,  756 
Hypertonic  solution,   6 
Hypertonicity,   63 
Hypogastric   nerves,    797 


Hypothyroidism,   755 

Hypotonic  solution,  6 
Hypozanthine,   635 


Ignition    juice,    438 

Ileocolic  muscles,  882 

Ileocolic  sphincter,  467,  469 

Imbibition,    62 

Imidazole  and  growth,  586,  604,  623 

Imidazole   ring,   02.". 

Imidazolylethylamine,  397,  426,  502 

Immediate  induction,  823 

Impulses,  nature  of,  830 

Index  test,  870 

Indican,   632 

Indicator  method,  list   of  indicators,  33 

Indole,   501,   604,   632 

Indoxyl   sulphate   of   potassium,   632 

Induction,   immediate,   823 

successive,  824 
Inhibition,  reciprocal,  814 
Inhibitory  effects  of  autonomic  nerves,  884 
Innervation,   reciprocal,   814 
Inorganic  constituents  of  urine,  531 
Inorganic   salts   and   growth,   586 
Inosine,  639 
Inosinic  acid,  637 

Inspiration,  negative  pressure  during,  305 
Integration   of  allied  reflexes,  822 
Integration   of  nervous  system,   809 
Intercostal  muscles,  319 
Internal  anal  sphincter  muscles,  882 
Internal   vesical  sphincter,   882 
Internal  respiration,  378 
Intestinal  bacteria,  657 
Intestinal   juice,    control   of,   442 
Intestinal  obstruction,  470,  504 
Intestinal   secretions,  441 
Intestine : 

absorption  from,  13 

anastomosis  of,  470 

bacterial  digestion  in,  499 

digestion   in,   489 
law  of,  466 

movements  of : 
large,  468 

clinical  conditions  effecting,  470 
small,  463 

nature  of,  466 
nervous   control   of,   467 
Intracardiac  pressure  curves,  146,  151 
Intracranial  pressure,  253 
Intragastric  pressure,  454 
Intrapleural  pressure,  304 
Intrapulmonic  pressure,  299 
Intra   vitam   anticoagulants,    100 
Intravascular  clotting,  107 
Inulin,  664 

Invertase,  81,  492,  657 
Invertebrates,    segmented,    783 
Inverting  enzymes,  657 


896 


INDEX 


Involuntary  fibers,  course  of,  879 

Iodine  value  of  fats,  688 

Ionization,   16 

Irradiation  in  nervous  system,  826 

Irreversibility   in   reflexes,   810 

Isoelectric  point,  64 

Isoleucine,   604 

Isomaltose,  79 

Isometric   period,   149 

Isotonic  solution,   6 


Jacksonian  epilepsy,  849 
Jugular  pulse  tracing,  274 
Juice,  gastric,  434 

intestinal,    I  12 

pancreatic,  441 


Keith    and    Flack,    conducting    tissue    in 

heart,  185 
Kent,  bundle  of,  183 
Ketonic  acid,  708 
Ketosis,  683 
Kidney,  oxygen   requirements  of,  396 

removal  of,  621 

structure  of,  507 
Knee-jerk,  804,  815,  828 

reinforcement  of,  829 


Lactalbumin,   577 

Lactam,    649 

Lactase,  491,  657 

Lactic  acid,  397,  603,  676,  665,  708 

effect   on   respiratory   center,   376 

in    mountain    sickness,   362 

produced   by   exercise,   367,  413 
Lactim,  649 
Language,  860 
Latent  period,  809 
Laws  of  gases,  336 

of  mass  action,  23 

applied   measurement    of    H-ion    concen- 
tration,  26 
Lead  poisoning,  650 
Lecithin,   689 

estimation   of,   697 

in  bile,  498 

in  blood,  696,  699 
Leech  extract,  100 
Legumelin,  578 
Legumin,  578 

Lesions    of    nervous    system,    835 
Leucine,  604,  666 
Leucocytes,    96 

sensitizing  of,   70 

transitorial,   97 
Leucocythemia,  648 
Levulose,  656 
Levy  and  Eowntree  method,  41 


Limulus,   heartbeat   of,   172 

Lipase,  25,  90,  491,  687 

Lipemia,  699 

Lipoids  of  blood,  699 

Lissauer-tract,   831 

List  of  indicators,  33 

Litten  's    diaphragm    phenomenon,    321 

Liver : 

circulation  through,   255 

disease  of,  620 

glycogen  in,  662 

metabolism  of  fats  in,  701 

perfusion  of,  618 

removal  of,  617 

urea  formation  in,   617 
Local  irritants,   243 
Localization,  cerebral,   843 
Locke    solution,    168 
Loven  reflex,  244 
Lungs,  circulation  through,  25:; 

mode  of  expansion  of,  325 
Lymph : 

absorption    into,    13 

electric    conductivity,    16 

nitration  in,   118 

formation  and  circulation,  115 

formation  of,  15 
Lymph  spaces,  115 
Lyinphagogues,  119 
Lymphatics,  115 
Lymphocytes,   96 
Lyophobe  colloids,  60 
Lysine,  592,  605 
Lysine  and  growth,  576 


M 


Macula?  aeustiese,  873 
Maintenance,   diets   for,   579 
Malingerers,  42 
Maltase,  491,  657 
Maltose,  491 
Manometer: 

blood-gas  differential,  382 

Hurthle,  124,  146 

mercury,   1 23 

optical,   146 

spring,  126 

valved  mercury,  152 
Mark-time  reflex,  806 
Mass  action,  23 

Mass   action   and   H-ion   concentration,   26 
Mass  movements  of  blood,   281 
Mastication,  444 
Mechanics  of  respiration,  299 
Medulla,  section  above,  839 
Megakaryocytes,  103 
Melting  point,  fats,  687 
Membrane  synaptic,   798 
Memory,  786 
Mercury   manometer,  123 


indi:x 


897 


Metabolism : 
calculations,  5 1 1 
endogenous,  615 
exogenous,  615 
general,  53-4 
in    starvation,    .~i><> 
normal,  570 
of  carbohydrates,  652 
of  fats,  686 
of   proteins,   595 
of  purines,  637 
special,  534 
Methyl   glyoxal,   665 
Methyl  group,  598 
Methyl   purines,   (>:;."i 
Methylation,  627 
Methylglyoxal,  665,  666 
Mett's  method,  487 
Microcytes,   94 
Microtonometer,  339 
Mid-capacity  of  lungs,  311 
Milk,  clotting  of,  488 
Miniature   stomach,   433 
Minimal  air,  300 
Mononuclear   leucocytes,   96 
Morawitz  theory,  blood  clotting,  107 
Motor   areas,   ablation   of,   843 

stimulation  of,  844,  846,  848 
Motor   nerves   of   segmental   duct   muscles, 

881 
Mountain  sickness,  360,  399 
adaptation   to,  400 
alveolar  CO.,  in,  360 
blood   corpuscles  in,  401 
Movements,  of  intestine,  463 

of   stomach,   452 
Municipal  food  statistics,  591 
Muscarine,  action  on  heart,  226 
Muscle,  cardiac,  properties  of,  17G 
refractory  period,   178 
respiration  in,   395 

staircase    phenomenon    (treppe),    177 
skeletal,   177 

respiration  in,   394 
Muscles,  antagonistic,  818 
Muscular  exercise,  243,  539 

circulatory   changes   during,   410 
effect  on  metabolism,  551 
effect  on  respiration,  366 
H-ion  during,  413 
purines   during,  647 
redistribution  of  blood   during,  415 
respiratory  changes   during,  410 
temperature  of   blood   during,   415 
Mutual   precipitation   of   colloids,   56 
Myenteric  reflex,  796 
Myogenic  hypothesis  of  heartbeat,  171 
Myxedema,  755 

energy  output  in,   542 

N 

Narcotics  and  blood  fat,  698 
Necrosis  of  liver,  620 


Negative  pressure  iii  ventricle,   L52 
Nephelometer,  697 

Nephrectomy,   (iii  1 
Nephritis,  650 

acidosis  in,  683 

urea  retention  in,  528 

Nerves: 
of  skin,  796 
network,   4,   29 

regeneration  of,  36 
segmental   distribution   of,   837 
specific  properties  of,  789 
vasodilator,    797 
Nerve  cells,  33,  799 
Xervi    erigentes,    231 
Nervous  control: 

of  gastric  secretion,  434 
of  ileocolic  sphincter,  468 
of   intestinal  glands,   44'_' 
of  intestinal  movements,  467 
of  pancreas,  427 
of  salivary  glands,  423 
of  stomach  movements,  458 
Nervous  diabetes,  672 

in  man,  674 
Nervous  system : 
autonomic,    877 
bulbar  fibers,   882 
functions  of,  884 
sacral  fibers,  882 
thoracicolumbar  fibers,   880 
effect  of  section  at  various  levels  of: 
anterior   root,   99,   835 
just  behind  medulla,  839 
just  behind  post.  corp.  quad.,  840 
just  in  front  of  ant.  corp.  quad.,  840 
posterior  roots,  836 
spinal   cord,   839 
evolution  of,  718 

influence  on  excretion  of  urine,  519 
integration  of,  786,  809 
Network,  nerve,  796 
neurofibrils,   800 
neuropile,   784,  797 
Neurogenic  hypothesis,  of  heart,  172 
Neurons,  784 

association,  783,  785 
intermediate,  802 
internuncial,  802 
Neutrality,  regulation  of,  36 
Nicotine,   233 

action  on  vagus,  226 
Nissl  bodies,  800 
Nitrogen: 

excretion   of,   premortal  rise,   560 
in  starvation,  566 
undetermined,   urine,   613 
Nitrogen  balance,  570 
Nitrogenous   constituents   of  urine,   523 
Nitrogenous  equilibrium,  571 
Nitrogenous     metabolites,     in     starvation, 
568 


898 


INDEX 


Nociceptive,   795,   804 

impulses,  832 

reflex,   825 
Noeud  vital,  327 
Nonelectrolytes,    16 
Nonthreshold  substances,  512 
Normal   acid,   22 
Normoblasts,  93 
Nuclease,  638 
Nucleic  acid,  637,  689 
Nuclein  ferments,  90 
Nucleins,  637 
Nucleoside,  638 
Nucleotide,   638 
Nystagmus,  871,  875 


O 


Obesity,  Banting  cure  for,  571 
Oleic  acid,   868 
Olein,  868 
Opsonins,  70 

Organs,  loss   of  weight   during  starvation, 
568 
perfusion  of,   618 
Ornithine,  616,  631 
Ornithinic  acid,  631 
Orthopnea,  313,  318 

Oscillatory  method  of   blood  pressure,  130 
Osmometer,  5,  230 
Osmosis,  4 
Osmotic  pressure,  4,  10 

and  formation   of   lymph,   13 
and   hemolysis,   7 
and  plasmolysis,  8 

measurement   by   depression   of   freez- 
ing point,   11 
in    physiologic    mechanisms,    13 
in  production  of  urine  by  kidneys,  14 
of  transfusates,  141 
Ovalbumin,   as   food,   577 
Ovovitellin,  as  food,  577 
Oxidases,   82 

Oxidation    of    blood,    387 
Oxybutyric  acid,  616,  683,  709 
Oxygen : 

coefficient  of  oxidation,  393 
determination  of,  562 
estimation  in  blood,  390 
requirements   of  tissues,   393 
tension  in  alveolar  air,     340,  344 
tension  in  arterial  blood,  337 
transportation  by  blood,  379 
volume  percentage  in  blood,  390 
Oxygen  insufficiency,  and  periodic  breath- 
ing,  373 
effect  of,  on  respiration,  350,   359 
Oxygen  supply  of  heart,  164 
Oxyproteic   acid,   629 


Pacchionian  body,  249 
Pain: 

sensation  of,  832 


Pain,  sensation  of — Cont  'd 
transmission  in  cord,   830 

sense,  795 
Palatability,  593 
Palmitic  acid,  686,  707 
Pancreas : 

hormone  control  of,  420 

histologic  changes  of,  429 

oxygen  requirements,  396 

nervous  control  of,  427 

sugar  metabolism  and,  678 
Pancreatic   diabetes,    678 
Pancreatic   digestion,   489 
Pancreatic  juice,  441 

and  fat  digestion,  690 

secretion  of,  420,  426 
Pancreatin,   490 
Parasympathetic  system,  882 
Paroxysmal  tachycardia,   269,   278 
Partial   dissociation,   271 
Partial  pressure   of   gases,   336 
Pathways,  sensory,  in  spinal  cord,  830 
Pelvic  ganglionic  group,  878 
Pentose,    664 
Pepsin,   action   of,   485 

products  of,  486 
Pepsinogen,  485 
Peptides,  601 
Peptone,  105,  486 
Perception,  861 
Perfusion,  of  kidney,  631 

of  liver,  618 
Perfusion   fluid,  of  heart,   165 
Perfusion  of  heart,  161 
Periodic  breathing,  causes  of,  372 

types   of,   371 
Peripheral  resistance,  134,   229 
Peristalsis: 

in  esophagus,  446 

in  large   intestine,   468 

in  small  intestine,   465 

in   stomach,  453,  456 
Peristaltic  rush,  466,  470 
Peristaltic  wave,  465 

Pernicious  anemia,   energy   output  in,  542 
Peroxidases,  82 
Ph,  27 

Phagocytes,   97 
Phenaceturic  acid,  710 
Phenol,   501 
Phenolacetic  acid,  502 
Phenolphthalein,  482,  525 
Phenylacetic  acid,  631,  710 
Phenylalanine,   604 
Phenyl  group,  604 
Phlorhizin,    664,    665 
Phosphates,  excretion  of,  47 
Phosphate  solutions   for   H-ion,   34 
Phosphates  of  urine,  532 
Phospholipins,  689 

in  bile,  498 
Phrenic   center,   328 
Physicochemical   basis,   1 


INDKX 


899 


Physiologic     processes     depending    on     ad- 
sorption,  69 
Pigments,    absorption    of,    117 
Pilocarpine,   action    on    heart,    L'L'li 
Tilomotor   fibers,   880 
Pitot's  tubes,  201 
Plasma,  99 
Plasmolvsis,  8 
Platelets,  of  blood,  97,  106 
Plethora,  86 

Plethysmograph,   209,   230,   273,   303 
Pleurisy,   .\2A 

Plexus  of  Auerbnch  and  Meissner,  466,  796 
Pneumothorax,  305 
Poikilocytes,  94 
Polygraph,  273 
Polyneuritis,  584 
Polynuelear  cells,  96 
Polypeptides,  487,  601 
Polyphosphoric  acid,   637 
Polysaccharides,  489 
Polysphygmograms,   273 
Portal  vein,  bloodflow  in,  255 
Postdicrotic  wave,  pulse,  203 
Postprandial   hyperglycemia,   659 
Postceutral  convolutions,   850,   854 
Posterior   roots,   787,   836 
Postsphygmic  period,   150 
Postural  reflexes,   826 
Potassium,  microchemieal  test  for,  421 
Potassium  ions,  on  heart,  167 
Potential  acidity  of  urine,  524 
Precentral  convolutions,  843,   854 
Precipitins,  595 
Predicrotic  wave,   pulse,   203 
Prefrontal  region,  854 
Premature  beats,   277 
Premortal  rise,   566 
Presphygmic  period,  149 
Pressor  impulses,  238,  239,  240 
Pressure: 

intrapleural,   304 

effect  of,  in  blood  pressure,  306 

intrapulmonic,  299 

negative,  305 

osmotic,  10 
Pressure  pulse,  127 
Principle  of  Willard  Gibbs,  66 
Proline,  604 

Proprioceptive  impulses,   865 
Proprioceptors,   822 
Prosecretin,   426 
Proteases,  89 
Protein  sparers,  571 
Proteinases,  80 
Proteins : 

as  colloids,  63 

bacterial  digestion  of,  501 

chemistry  of,  597 

metabolism  of,  595,  613 
end  products,  613 

minimum   requirement,   572,   592 

of  blood,  88 


Proteins — Cont  'd 

relative  value  of,  for  growth,   Gil 

salting  out  of,  60 
Proteose,  486 
Protopathic   impulses,   831 
Protopathic  receptors,  790 
Protothrombin,   103,   106,   111 
Psychopathology,  862 
Ptomaines,   502,   629 
Ptyalin,  491,   656 
Pulmonary  circulation,  253 
Pulmonary  ventilation,  350 
Pulses,  198 

abnormal,  276 

alternans,  181 

bigeminus,  181 

contour  of  wave,  200 

length  of  wave,  199 

palpable,  201 

pressure,  127 

pulse  curves,  202 

pulse  waves,  189,  200,  203 

rate  of  transmission,  198 

velocity,  200 

venous,  central,  205,  274 

venous,   peripheral,   205 
Purkinje  fibers,   184 
Purine   bodies    (see  Purines) 
Purines : 

chemistry  of,  529,  613,  634 

endogenous,  641,   643 

exogenous,  641 

metabolism  of,  637 

in  starvation,  569 

synthesis  of,  646 
Putrefaction,  intestinal,  501,  530 
Putrescinc,   629 
Pyloric  canal,  452 
Pyloric  sphincter,  control  of,  456 
Pyloric  vestibule,  453 
Pyramidal  cell  lamina,  854 
Pyrrolidine  bases,  636,  637 
Pyruvic  acid,   600,   708 


R 


Kami  communicantes,  233 

Raynaud's  disease,  bloodflow  in,  258 

Reaction  deviation,  871 

Reaction  of  urine,  524 

Reactions    depending   on    adsorption,    66 

Reactions  of  body  fluids,  35 

Receptors,  782,  788 

distance,   785 

epicritic,   790 

external,  788,  822 

internal,  788 

of  skin,  790 

projicient,   785,   788 

proprio,  822 

protopathic,  790 

temperature,  791 

touch,  793 


900 


INDEX 


Reciprocal  inhibition,  814 

action  of  strychnine  on,  819 
Reciprocal    innervation    of    blood    vessels, 

241,  814 
Bed  blood  corpuscles,  origin  of,  92 
Eeduction  of  blood,  387 
Eeferred  pain,  885 
Keflex,  conditioned,  431 

unconditioned,  431 
Keflex  arc,  784 

after  effect,  810 

grading  of  intensity,  809 

irreversibility   of   conduction,   810 

latent  period,  809 

oxygen  deprivation,  813 

properties  of,  13,  29,  49 

refractory  period,  811 

summation,  810 
Reflex  conduction,  resistance  of,  813 
Reflexes : 

allied,   simultaneous   integration   of,   823 

antagonistic,  824 

axon,  797 

Babinski,   807 

conditioned,  856 

cremasteric,    856 

crossed  extension,   804 

extensor  thrust,  805 

fatigue  of,  825 

flexion,  804,  821 

integration  of  allied,  821 

interaction  between,  821 

irradiation  of,  826 

mark-time,   806 

myenteric,    796 

nature  of,  825 

nociceptive,  825 

postural,   826 

unconditioned,  431,  856 
Refractive  index,  blood,  88 
Refractory  period,   811 
Refractrometric  methods,  88 
Regeneration  of  erythrocytes,   93 
Regulation  of  neutrality,  36 
Regurgitation  of  gastric  contents,  449 
Reichart-Meissl  value  of  fats,  688 
Reinforcement  of  knee-jerk,  829 
Renal  diabetes,  661 
Renal  function,  theories  of,  511 
Rennin,  488 

Reserve  alkalinity,  measurements  of,  indi- 
rect methods,  42,  46 
measurement  of,  titration  methods,  41 
Residual  air,  300,  311 
Respiration: 

abdominal,    307 

beyond  the  lungs,  378 

during  muscular  exercise,  410 

in  compressed  air,  402 

in  rarefied  air,  399 

mechanics  of,  299 

movements  of  diaphragm  in,  321 

movements  of  ribs  in,  319 


Respiration  calorimeter,  536 
Respiratory  center,  327 

afferent  impulses  to,  331,  332 

automaticity  of,  329 

hormone  control  of,  335,  349 

reflex    control    of,    331 

sensitivity  to  alveolar  C02,  357 

stimulation  by  CO,,  352 

subsidiary,  328 
Respiratory  changes  in   muscular   exercise, 

410 
Respiratory  exchange : 

according  to  body  weight,  550 

and  body  temperature,  551 

clinical   method   for   determining,   554 

in  diabetes,  678 

and  muscular  exercise,  551 

and  temperature  of  environment,  551 

in  tissues,  393,  397 
Respiratory  hormone,  nature  of,  349 
Respiratory  movements,  315 
Respiratory  passages,   pressure   of   air   in, 

299 
Respiratory  quotient,   545 

in  diabetes,  678 

influence  of  diet  on,  547 

influence  of  metabolism  on,  549 

influence  of  muscular  activity  on,  370 
Respiratory  tracings,   303 
Respiratory  valves,  Pearce's,  554 
Reticulated  erythroblasts,  93 
Reversible  action  of  enzymes,  25 
Ribs,  movements  of,   315 
musculature  of,  319 
undulatory   movements   of,   317 
Right  lateral   connection,   heart,   185 
Rigidity,  decerebrate,  808 
Rolandic  fissure,   855 
Roots,  787 

anterior,  787,  835 
posterior,  787,  836 
Rhythmic   segmentation,   464 


S 


Sacral  outflow,  882 

Salicylates,  648,  657 

Saline  iniection,  effect  on  blood  pressure, 

139 
Saliva,   control   of  secretion,  nervous,  423 
psychic,  431,  856 
normal  secretion,  431 
Salt,   dietetic  value,   586 
Salted  blood,  100 
Salting  of  proteins,  60 
Saponification,  687 
Sarcosine,    623 
Saturation  limits,   652,   654 
Scratch  reflex,  805,  821 
Scurvy,  585 

Sea  anemone,  nervous  system  of,  783 
Second  wind,  415 
Secretory  fibers,  varieties  of,  424 


TNDKX 


'Mil 


Becretin,   125 

chemical  nature  of,  426 

mechanism  of  action  of,  420 
Secretion  (sec  under  various  glands) 

general    considerations,    418 
Segmental  distribution  of  nerves,  837 
Segmentation  movements,  463 
Segmented  invertebrates,   nervous  system, 

783 
Semicircular  canals,   873 

eye  movements  and,   875 
removal  of,  874 
Semilunar  valves,  150,  155 
Semipermeable   membrane,   4 
Sense,    temperature,    701 

touch,   793 

pain,  795 
Sensory  centers,  8.10,  851 
Serine,  603 
Serum   albumin,   87 
Serum  globulin,  87 
Sex,   effect  on   creatinine  excretion,   624 

effect  on  energy  output,  541 
Sham   feeding,   435 
Shell  shock,  287 
Shock,  287 

anesthetic,  288 

blood  pressure  in,  290 

experimental   investigations,    289 

gravity,   287 

hemorrhagic,   288 

nervous,   289 

recovery  from,   805 

secondary  symptoms  of,  295 

spinal,  288,   803 

surgical,  289 

treatment  of,  295 

vasomotor  control  in,  290 
Sinoauricular  node,   185,   266 
Sinus  arrhythmia,   266,  277 
Sinus  bradycardia,  266,  277 
Skatole,  501,  632 

in  urine,  531 
Skeletal  muscle,  respiration  in,  394 
Skin,  receptors  of,  790 
Soap,  686 
Sodium  ions,  166 
Solution  of  gases,  336 
Solutions: 

gas  laws  and,  3 

gram  molecular,  5,   22 

hypertonic,  hypotonic,  and  isotonic,   6 

nature   of,   3 
Sorensen     method     for    estimating    amino 

groups,  599 
Sounds,  cardiac,  157 

recording  of,  158 
Specific  conductivity,   17 
Specific  dynamic  action,  538 
Specific  gravity  of  urine,  522 
Sphingomyelin,   689 
Sphygmic   period,   273 
Sphygmograph,  Dudgeon's,  201 


Spinal    animal,    Sii  I 

Spinal  column,  786 
Spinal    cord : 

ablation   of,    .S : : < > 

in  laboratory  animals,  803 
in  man,  806 
hemisection  of,  831 
sensory   pathways  in,  830 
successive   defeneration   in,   813 

spinal  pathways,  afferent,'  830 

Spinal  shock,  803,  807 

Spirometer,   556 

Splanchnic    circulation    in    shock,    2!)2,    L'!>  I 

Splanchnic   nerve,   233,   672 

Sponges,   nervous  system   o£,   782 

Stalagmometer,  65 

Standard   of   neutrality,   26 

Standard   solutions,  preparation   of,  34 

Stannius'  ligature,  176 

Starvation,  566 

acidosis  during,  569 

cause  of  death,  570 

effect  of  creatinine  excretion,  625 

energy   output   during,  568 

excretion  of  nitrogen,  566 

loss   of  weight,  568 

nitrogenous   metabolism,   568 

purines   during,   569 

secretion  of  gastric  juice  during,  476 

sensations   during,   475 

sulphur  during,  569 

treatment  of  diabetes,  684 
Statistical   method,   in  diet   control,   589 
Stearic   acid,   687 
Stokes-Adams  syndrome,  193 
Stomach: 

arrangement  of  food  in,  455 

digestion  in,  481 

emptying  of,  456 

effect     of     pathologic     conditions     on, 

460 
rate  of,  458 

gas   in,   462 

miniature,  433 

movements  of,  451 
effect  on  food,  454 
Stroma  of  red   cell,  91 
Stromuhr,  207 
Strychnine,  action  on  reciprocal  inhibition, 

819 
Subarachnoid  space,  116,  248 
Subcostal  angle,  321 
Subcostal   borders,   321 
Subdural  space,  116 
Submicrons,   54 
Substantia-gelatihosa,  831 
Successive  induction,  824 
Successive  regeneration,  813 
Sugar,  storage  of,  662 
Sugar  level  in   blood,  657 
Sugar    metabolism     (sec    Carbohydrates), 
652 
relation  of  pancreas  to,  678 


902 


INDEX 


Sulphates,  ethereal,  632 
Sulphates,  of  urine,  532 
Sulphur,   excretion   of,   614 

in   starvation,   569 
Summation  in   reflexes,   810 
Superior  laryngeal  nerve,  influence  on  res- 
piration,   33-4 
Supplemental  air,  300 
Surface  area,  and   energy   output,   540 
Surface  tension,  measurement  of,  64 
Surgical  shock,  289 
Survival  period,  580 
Suspensions,   51 
Suspensoids,  colloids,  60 
Swallowing,  445 

center,    447 

of  liquid  food,  448 

nervous  control  of,  447 

sounds  produced  by,  449 

x-ray  during,  449 
Sweat  glands,  880 
Sympathetic   control   of   heart,   227 

"afferent,   223 
Sympathetic  nerve,  424 
Sympathetic  system,  878,  880 
Synapsis,  784,"  797,  819 
Synaptic  fatigue,   296 
Synaptic   membrane,   798 
Syntonin,  486 
Systolic  index,  128 
Systolic   pressure,    127 

measurement  of,  in  man,  128 


T 


Tabes  dorsalis,  286 
Tachycardia,  paroxysmal,  269 
Tactile  impulses,   833 

transmission  in  cord,  833 
Taurine,  494 
Taurocholic  acid,  494 
Temperature : 

after-effect,  792 

effect  on  metabolism,  551 

sensation  of,  792,  832 

transmission    in    cord,    832 
Temporary  association,   857 
Tendon  jerks,  828 
Tension  of  C02  in  venous  blood,  342 

of  gases  in  alveolar  air,  46,  339 
Tetanus,  in  stomach,  471 
Tetanus   toxin,   action   on   reciprocal   inhi- 
bition,  819 
Theine,  635 
Theobromine,   635 
Thermoesthesiometer,  791 
Thoracic  operculum,  316 
Thoraeicolumbar  outflow,  880 
Thrombin,  102 
Thrombogen,  106 
Thrombokinases,   106 
Thromboplastin,  106,  111 
Thrombosis,  107 


Thrombus  formation,   113 
Thymic  acid,   649 
Thymine,  637 
Tidal  air,  300 
Tissot   method,   544,   55(5 
Tissue  fluid,  116 
Tissue   juice,    117 
Tissues: 

amino  acids  in,  607 

influence  of,  on  clotting,  104 

oxygen   requirements   of,   393,   397 

utilization  of  glucose  by,  681 
Titrable  aciditv  and  alkalinity,  22 
Tonometer,   338,   381 
Tonus  rhythm,  of  stomach,  471 
Torcular  herophili,  250 
Touch,   discrimination,   794 

localization,  37,   795 

sense,   793 
Toxins,  69 

Transfusion    of   blood,    135,    139 
Trephining,    253 
Treppe,  178 
Trichlorlactamide,   635 
Trimethylamine,   629 
True  colloidal  solutions,  51 
Trvpsin,  426,  428,  601 

action    of,    489 
Tripsinogen,  426,  428 
Tryptophane,   592,   596,   604,   632 

and  growth,  576,  578 
Tubules,  uriniferous,  function  of,  517 
Tumors  and  diet,  582 
Turbidity  of  colloids,  51 
T unk's  method,  115,  842 
TyndaU  phenomenon,  colloids,  51 
Tvrodes  solution,  168 
Tyrosine,   502,   604,  632,   666 
Tryptic   digestion,   products  of,  490 


U 


Ultramicroscope,   800 
Uncompensated  acidosis,  39 
Unconditioned   reflex,  431,   856 
Undetermined  nitrogen,   613,   629 
Undulatory   movement  of   ribs,   317 
Urea,  527,  608 
in  blood,  610 

during   disease,   651 
excretion   of,   615 
Urease,  82,  610 
Uric  acid,  529,  531,  614,  618 

amount  of,  522 

bases  of,  531 

chemical  nature  of,  634 

endogenous  excretion,  647 

in   disease,   651 

metabolism  of,  643 

of  blood,  648 

synthesis   of,   644 

under  drugs,  648 
Uric  acid  diathesis,  634 


I  MUX 


003 


Uricase,   640 
(Jricemia,   650 
Uricolytic  index,  6 1 1 
Orine : 

ileitis   of,   531 

amino  acid,  530 

aromatic  oxyacida  of,  530 

chlorides  of,  531 

composition,  521 

creatinine  of,  529 

depression  of  freezing  point  of,  523 

hippuric  acid,  530 

homogentisic  acid,  531 

inorganic  constituents  of,  531 

nitrogenous  constituents  of,  523 

normal   organic  salts  of,  523 

phosphates,  532 

physical    processes    involved    in    produc- 
tion  of,   14 

purine  bodies  of,  529 

rate  of  excretion,   643 

refection  of,  524 

skatole,   531 

solid  constituents  of,  525 

specific  gravity  of,  522 

sulphates  of,  532 

total  potential  acidity  of,  524 

urea  of,  527 
Oriniferous  tubule,  507 
Urobilinogen,  496 
Utilization  limit,  653 


Vagus,   878 

control  of  heart,  217 
impulses,  afferent,  222 
Vagus  center,  effect  of  nicotine  on,  226 
location   of,   222 
tonicity  of,  221 
Vagus  nerve,  influence  on  respiration,  332 
Valine,  604,  606 

Valves,   cardiac,  mechanism  of,  154 
auriculoventricular,    154 
semilunar,  155 
Van  Slyke  method  for  acidosis,  42,  44 
Van  Slyke  method  for  amino  groups,  600 
Vascular  reflex,  283 
Varicose  veins,  214 
Vasoconstriction,  229 
Vasoconstrictor  fibers,   229 

methods  of   detecting,   229 
of  extremities,  233 
of  head,  233 
of    viscera,    233 
origin  of,   232 
Vasodilator   fibers,   234 

methods   for  detecting,  229 
origin  of,  234 
Vasodilator  nerves,  797 
Vasomotor  center : 

afferent  impulses,  238,  239 

chief  center,  235 

effect  of  H-ion  of  blood  on,  238 


Vasomotor  center — Coni  M 

hormone   control   of,   237 

subsidiary  centers,  235 
Vasomotor   fibers,   231 

origin  of,  232 
Vasotonic  impulses,  240 
Veins,  disappearance  of  pulse  in,  205 
Velocity   constant,   enzymes,    75 
Velocity,  mean  lineal,  206 

pulse,  200 
Venous  blood,  tension  of  CC>,  in,  312 
Venous  outflow,  230 
Venous  pulse  tracing,  273 
Venous  return  to  heart,  292 
Venous  sinus,  248 
Ventilation  of  lungs,  350 
Ventricle,  curves  of  pressure  in,  146,   148, 

151 
Ventricles : 

conductivity  tissue  of,  184 

fibrillation,  195 

spread  of  beat  in,  192,  194 
Vignin,   578 

Viscera,  blood  supply  of,   247 
Visceral  bloodflow,  212 
Visceral   sensitiveness,   885 
Viscosity  of  blood,  140 
Visual  center,  851 
Visual  psychic  areas,  854 
Visual   sensory   area,   854 
Vital  activity,   14 
Vital  capacity,  300,  313 

in  disease,  314 
Vital  theory  of  urine  excretion,   572 
Vitamines,  584 
Vividiffusion,  606 
Volition,   786 
Vomiting,  449 


W 


Water  content  of  blood,  86 
Water   hammer, 

in  blood  pressure  measurement,  133 
Wheatstone  bridge,  18 
White  crescentic  line,  226 
Wiggers  manometer,  146 
Willard  Gibbs,  principle  of,  66 
Word  blindness,   863 
Word   centers,   862 
Word  deafness,  863 


Xanthine,  635 

Xanthine  oxidase,  639 

Xanthosine,  639 

X-rays,  in  study  of  stomach,  433 

movements   of   stomach   seen   by  aid   of, 
451 


Zein,  inadequacy  for  growth,  578 
Zymogen  granules,  420,  421,  429 


QP34 


J 


M22 


Maoleod 

Physiology  and  biochemistry  in 
modern  me/iicine. 


QP3^ 


Mii 


